Renzo Luisi

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

Aziridinyl Anions: Generation, Reactivity, and Use in Modern Synthetic Chemistry

Aziridines, nitrogen-containing three-membered ring heterocycles, are well established useful and versatile building blocks in organic synthesis and medicinal chemistry.1 Although less common than the corresponding oxygensubstituted heterocycles, the aziridine functionality is present in many naturally occurring molecules showing significant biological properties, such as azinomycins, mitomycins, ficellomycin, miraziridine, and maduropeptin (Figure 1). In view of this, aziridines have been extensively investigated either from the synthetic or reactional points of view. Concerning the reactivity, the most common transformations of these spring-loaded three-membered ring systems are the ring-opening reactions that can be initiated by both electrophilic and nucleophilic reagents.2 Concerning the synthetic methodologies developed for the preparation of aziridines, the main ones are based on cyclization reactions, transfer of nitrogen to olefins,3 transfer of carbon to imines,4 addition across the carbon-nitrogen double bond of azirines,5 reactions of ylides,6 aza-Darzen approaches,7 and ring contraction.8 Another methodology that has gained importance recently is based on the use of metalated aziridines (commonly called aziridinyl anions). The * E-mail addresses: florio@farmchim.uniba.it; luisi@farmchim.uniba.it. Saverio Florio received his “Laurea” in Chemistry at the University of Bari (Italy). After being first Assistant Professor and then Associate Professor of Organic Chemistry in 1986, he was appointed Full Professor of Organic Chemistry at the University of Lecce. In 1990, he moved to the University of Bari as the chair of organic chemistry. Currently, he is Director of “Consorzio Interuniversitario sulle Metodologie e Processi Innovativi di Sintesi” (CINMPIS). President of the Division of Organic Chemistry of the Italian Chemical Society from 1997 to 2001, at present he acts as the vice president of the Italian Chemical Society. He is a member of the Scientific Advisory Board of the Ischia IASOC School and member of the “Academy of Science and Arts of Salsburg”. Prof. Florio’s research interests are concerned with mechanistic studies, stereochemistry, and asymmetric synthesis of small-ring heterocycles. Prof. Florio has published more than 200 papers and for his research work has been awarded with “ZieglerNatta Lecture” from the German Chemical Society (GDCh) in 2005 and with the “Angelo Mangini Gold Medal” from the Division of Organic Chemistry of the Italian Chemical Society in 2007. Chem. Rev. 2010, 110, 5128–5157 5128

Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides

Abstract A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of nitrogen without the requirement for either preactivation or for metal catalysts. Mixing ammonium salts with diacetoxyiodobenzene directly converts sulfoxides into sulfoximines. This report describes the first example of using of ammonia sources with diacetoxyiodobenzene to generate an electrophilic nitrogen center. Control and mechanistic studies suggest a short‐lived electrophilic intermediate, which is likely to be PhINH or PhIN+.

Synthesis of optically active arylaziridines by regio- and stereospecific lithiation of N-Bus-phenylaziridine

Alpha,alpha-disubstituted aziridines can be produced in good yields by selective lithiation of N-tert-butylsulfonyl-2-phenylaziridine (n-BuLi/TMEDA, Et(2)O) at the benzylic position and subsequent trapping with a range of electrophiles. Repetition of the lithiation/electrophilic trapping sequence provides a stereocontrolled route to trisubstituted aziridines. Using (R)-N-tert-butylsulfonyl-2-phenylaziridine, the alpha,alpha-disubstituted aziridines can be produced as single enantiomers (er >98:2), indicating that the intermediate organolithium is configurationally stable. Efficient aziridine ring-opening reactions leading to 1,2-diamines and 1,4-diamines are also reported.

New anti-viral drugs for the treatment of the common cold

Human Rhinovirus (HRV) is the most important aetiologic agent of common cold in adults and children. HRV is a single-stranded, positive sense RNA virus and, despite the high level of conservation among different serotypes, sequence alignment of viral protease 3C with mammalian protease reveals no homology. Thus, protease 3C is an optimal target for the development of anti-HRV agents. In the present work we investigated the design, the synthesis and the development of new potential reversible inhibitors against HRV protease 3C. Docking studies on the crystallized structure of HRV2 protease 3C led us to the design and the synthesis of a series of 3,5 disubstituted benzamides able to act as analogues of the substrate. We also developed 1,3,5 trisubstituted benzamides where aromatic substitutions on the aryl ring led us to investigate the importance of pi-pi interaction on the stabilization of protease 3C-inhibitor complex. All structures were tested for enzymatic inhibition on HRV14 protease 3C. Results highlighted the inhibitory activity of compounds 13, 14, and 20 (91%, 81%, and 85% at 10 microM, respectively), with the latter exhibiting an ID(50) (dose that inhibits 50% of the viral cytopathic effect) on HRV-14=25 microg/ml.

Α-vs Ortho-Lithiation of N-Alkylarylaziridines : Probing the Role of the Nitrogen Inversion Process

The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated exclusively at the alpha-position. Evidence is reported that ruled out the possibility that the alpha-lithiation, observed for the diphenylaziridines, is the result of an ortho- to alpha-translocation phenomenon, thus substantiating a direct alpha-deprotonation process. The role of the aziridine nitrogen lone-pair has been considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it is possible to generate with high regioselectivity alpha- and/or ortho-lithiated aziridines, which can be stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of diphenylaziridines is made possible by halogen- or tin-lithium exchange and by deprotonation of bis-deuterated aziridines.

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

Microreactor technology and flow chemistry could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chemistry, catalysis, hazardous chemistry and continuous flow processing are described. Selected examples highlight the role that flow chemistry could play in the near future for a sustainable development.

Synthesis of Sulfoximine Carbamates by Rhodium-Catalyzed Nitrene Transfer of Carbamates to Sulfoxides

Sulfoximines are of considerable interest for incorporation into medicinal compounds. A convenient synthesis of N-protected sulfoximines is achieved, under mild conditions, by rhodium-catalyzed transfer of carbamates to sulfoxides. The first examples of 4-membered thietane-oximines are prepared. Sulfoximines bearing Boc and Cbz groups are stable to further cross coupling reactions, and readily deprotected. This method may facilitate the preparation of NH-sulfoximines providing improved (global) deprotection strategies, which is illustrated in the synthesis of methionine sulfoxide (MSO).

Lithiation of N-alkyl-(o-tolyl)aziridine: stereoselective synthesis of isochromans.

The lithiation reaction of o-tolylaziridine 1 has been investigated by using the aziridine ring capability to act as a directing metalation group. Trapped with electrophiles, the resulting o-aziridinyl benzyllithium 1-Li gives access to several functionalized aziridines 2a-j. The hydroxyalkylated derivatives 2d-j were converted into important scaffolds such as isochromans 3a-d. A stereoselective preparation of isochromans (R)-3b, (1R,3S)-3d, and (1R,3R)-3d has been developed starting from enantioenriched o-tolylaziridine.

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.