Enrique E. Maroto

Chiral Fullerenes from Asymmetric Catalysis

Fullerenes are among the most studied molecules during the last three decades, and therefore, a huge number of chemical reactions have been tested on these new carbon allotropes. However, the aim of most of the reactions carried out on fullerenes has been to afford chemically modified fullerenes that are soluble in organic solvents or even water in the search for different mechanical, optical, or electronic properties. Therefore, although a lot of effort has been devoted to the chemical functionalization of these molecular allotropes of carbon, important aspects in the chemistry of fullerenes have not been properly addressed. In particular, the synthesis of chiral fullerenes at will in an efficient manner using asymmetric catalysis has not been previously addressed in fullerene science. Thus, despite the fact that the chirality of fullerenes has always been considered a fundamental issue, the lack of a general stereoselective synthetic methodology has restricted the use of enantiopure fullerene derivatives, which have usually been obtained only after highly expensive HPLC isolation on specific chiral columns or prepared from a pool of chiral starting materials. In this Account, we describe the first stereodivergent catalytic enantioselective syntheses in fullerene science, which have allowed the highly efficient synthesis of enantiomerically pure derivatives with total control of the stereochemical result using metallic catalysts and/or organocatalysts under very mild conditions. Density functional theory calculations strongly support the experimental findings for the assignment of the absolute configuration of the new stereocenters, which has also been ascertained by application of the sector rule and single-crystal X-ray diffraction. The use of the curved double bond of fullerene cages as a two-π-electron component in a variety of stereoselective cycloaddition reactions represents a challenging goal considering that, in contrast to most of the substituted olefins used in these reactions, pristine fullerene is a noncoordinating dipolarophile. The aforementioned features make the study of stereoselective 1,3-dipolar cycloadditions onto fullerenes a unique scenario to shed light onto important mechanistic aspects. On the other hand, the availability of achiral starting materials as well as the use of nonexpensive asymmetric catalysts should provide access to chiral fullerenes and their further application in a variety of different fields. In this regard, in addition to biomedical applications, chiral fullerenes are of interest in less-studied areas such as materials science, organic electronics, and nanoscience, where control of the order and morphology at the nanometer scale are critical issues for achieving better device efficiencies.

Stereodivergent Synthesis of Chiral Fullerenes by [3 + 2] Cycloadditions to C60

A wide range of new dipoles and catalysts have been used in 1,3-dipolar cycloadditions of N-metalated azomethine ylides onto C60 yielding a full stereodivergent synthesis of pyrrolidino[60]fullerenes with complete diastereoselectivities and very high enantioselectivities. The use of less-explored chiral α-iminoamides as starting 1,3-dipoles leads to an interesting double asymmetric induction resulting in a matching/mismatching effect depending upon the absolute configuration of the stereocenter in the starting α-iminoamide. An enantioselective process was also found in the retrocycloaddition reaction as revealed by mass spectrometry analysis on quasi-enantiomeric pyrrolidino[60]fullerenes. Theoretical DFT calculations are in very good agreement with the experimental data. On the basis of this agreement, a plausible reaction mechanism is proposed.

Hierarchical Selectivity in Fullerenes: Site‐, Regio‐, Diastereo‐, and Enantiocontrol of the 1,3‐Dipolar Cycloaddition to C70

Since the discovery of fullerenes and their further preparation on a multigram scale, these molecular carbon allotropes have been thoroughly investigated from the chemical viewpoint in the search for new modified fullerenes that are able to exhibit unconventional properties for practical applications. Furthermore, this knowledge has allowed a faster and better understanding of the chemical reactivity of the related carbon nanostructures, in particular of the promising carbon nanotubes, endohedral fullerenes, and the most recent graphenes. However, the number of studies on the reactivity of higher fullerenes is comparatively scarce and the use of asymmetric catalysis in these systems has been neglected so far. Higher fullerenes include a great diversity of molecules with different structures and chemical behavior that, because of the minor degree of symmetry, give rise to a complex covalent chemistry, in which chirality is an important and fascinating aspect. The preparation of chiral fullerenes has been based on chiral starting materials or, alternatively, on the most common racemic syntheses followed by complex, expensive, and highly time-consuming chromatographic isolation and purification processes. However, even when the isolation of the different isomers is feasible, the high costs and low abundance of higher fullerenes make necessary the availability of an efficient synthetic methodology to limit a broad distribution of products. Recently, we reported a straightforward procedure catalyzed by silver or copper acetate to efficiently obtain pyrrolidino[60]fullerenes with stereochemical control by enantioselective cycloaddition of azomethine ylides to the C60 molecule. [8] However, the extension of the scope of such a methodology to higher fullerenes, namely C70, is not a trivial process because C70 has to face many distinct levels of selectivity. Unlike C60, C70 lacks a spherical symmetry and has four different types of double bonds on the cage. The most common additions to [70]fullerene proceed in a 1,2 manner with a regioselectivity driven by the release of the strain of the double bond. Accordingly, additions occur preferentially at the most strained fullerene double bonds, namely those located at the polar zone (a site followed by b and g sites). The flatter equatorial region is less reactive and the addition only rarely takes place at the double bond of the d site. Particularly, cycloadditions of azomethine ylides typically give rise to the a, followed by the b, and a small amount of the g regioisomers (C(8) C(25), C(7) C(22), C(1) C(2) according to the systematic numbering; Figure 1). We propose to refer to these isomers (a, b, etc.) and to this form of selectivity as “site isomers” and site selectivity, respectively, to distinguish them from the regioisomers that result from the addition of nonsymmetric 1,3-dipoles to a double bond of the fullerene sphere. Indeed, depending on the orientation of the asymmetric azomethine ylide addition to the fullerene double bond, two regioisomers are, in turn, possible for each of the formed cycloadducts (see Figure 1). Furthermore, each of these regioisomeric pyrrolidines could be formed in a cis or trans configuration (diastereomers) and, in turn, in both of the enantiomeric forms. Herein we describe an efficient catalytic site-, regio-, diastereo-, and enantioselective cycloaddition of N-metalated azomethine ylides to C70 at low temperatures and while maintaining the atom economy principle. This methodology [*] E. E. Maroto, Dr. S. Filippone, Dr. . Mart n-Domenech, Prof. Dr. N. Mart n Departamento de Qu mica Org nica I Facultad de Ciencias Qu micas Ciudad Universitaria s/n, 28040 Madrid (Spain) Fax: (+ 34)91-394-4103 E-mail: nazmar@quim.ucm.es Homepage: http://www.ucm.es/info/fullerene

Switching the Stereoselectivity: (Fullero)Pyrrolidines “a la Carte”

Stereodivergent syntheses of cis/trans pyrrolidino[3,4:1,2]fullerenes and endo/exo pyrrolidines are reported with high enantioselectivity levels. Fullerenes are revealed as a useful benchmark to develop suitable catalysts to control the stereochemical outcome and to shed light on the mechanism involved in the related 1,3-dipolar cycloaddition.

Enantiospecific cis-trans isomerization in chiral fulleropyrrolidines: hydrogen-bonding assistance in the carbanion stabilization in H2O@C60.

The stereochemical outcome of cis-trans isomerization of optically pure [60], [70], and endohedral H2O@C60 fulleropyrrolidines reveals that the electronic nature of substituents, fullerene size, and surprisingly the incarcerated water molecule plays a crucial role in this rearrangement process. Theoretical DFT calculations are in very good agreement with the experimental findings. On the basis of the experimental results and computational calculations, a plausible reaction mechanism involving the hydrogen-bonding assistance of the inner water molecule in the carbanion stabilization of endofullerene is proposed.

Mass Spectrometry Studies of the Retro-Cycloaddition Reaction of Pyrrolidino and 2-Pyrazolinofullerene Derivatives Under Negative ESI Conditions

Substituted pyrrolidino- and 3-alkyl-2-pyrazolinofullerenes ionize under ESI and MALDI mass spectrometry conditions and negative mode of detection undergoing mass spectral fragmentations, which can be easily correlated with the reported results for the thermal and electrochemical retro-cycloaddition reactions of these compounds. 2-Pyrazolinofullerenes lead directly to a [60]fullerene product ion formed through a retro-cycloaddition process regardless of the substituents attached at the carbon and nitrogen atoms of the heterocyclic ring. These results are different from whose reported for the thermal and electrochemical processes. In contrast, pyrrolidinofullerenes undergo different fragmentative reactions depending upon the substituents (hydrogen, alkyl, or acyl) attached at the nitrogen atom of the heterocyclic ring leading eventually to the pristine C60 in the last step of the fragmentation pathway.

Diastereoselective Synthesis of C60/Steroid Conjugates

The design and synthesis of fullerene-steroid hybrids by using Pratos protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C60, thus ascertaining the proposed structures.

Competitive retro‐cycloaddition reactions in heterocyclic fullerene bis‐adducts ions: selective removal of the heterocyclic moieties

RATIONALE We have investigated the fragmentation reactions of ions from bis-adducts containing isoxazolino-, pyrrolidino- and methanofullerene moieties. METHODS The fragmentation reactions induced by collision-induced dissociation (CID) of ions generated under electrospray ionization (ESI) in positive and negative modes of detection using an ion-trap spectrometer have been investigated. RESULTS The competitive retro-cycloaddition process between isoxazoline and pyrrolidine rings fused to [60]fullerene reveals that it is strongly dependent on the experimental negative or positive ESI experimental conditions. Thus, whereas retro-cycloaddition reaction is favored in the pyrrolidine ring under negative conditions, the protonation occurring on the nitrogen atom of the pyrrolidine ring under positive conditions precludes its retro-cycloaddition and, therefore, only the isoxazoline ring undergoes the retro-cycloaddition process. The obtained experimental results are different from those reported when the reaction is carried out under thermal conditions. Competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show that the heterocyclic ring undergoes cycloelimination, leaving the methanofullerene moiety unchanged. In this case, the same selectivity is observed under thermal and gas-phase conditions. CONCLUSIONS The observed selectivity in the heterocyclic removal in these [60]fullerene derivatives is reversed from negative conditions (radical anions) to positive conditions (protonated molecules). Moreover, the retro-cycloaddition reaction behaves differently under spectrometric and thermal conditions.

Catalytic Stereodivergent Synthesis of Steroid–Fulleropyrrolidine Hybrids

The diastereoselective synthesis of cis and trans steroid-fulleropyrrolidines hybrids by reaction of N-metalated azomethine ylides [Cu(II) or Ag(I)] with the appropriate chiral ligand and C60 is described. The experimental findings reveal that the azomethine ylide stabilized by an allylic group cycloadds to [60]fullerene in an efficient manner and with a good diastereomeric excess. Furthermore, the new generated stereocenters are fully controlled by the catalytic systems used without being influenced by the chirality of the steroid. Interestingly, by this synthetic methodology the each one of the four possible stereoisomers have efficiently been obtained and characterized by CD spectra.