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.

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.

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.

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.

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.

Dumbbell-type fullerene-steroid hybrids: a join experimental and theoretical investigation for conformational, configurational, and circular dichroism assignments.

New [60]fullerene-steroid conjugates (4-6) have been synthesized by 1,3-dipolar cycloaddition and Bingel-Hirsch cyclopropanation reactions from suitably functionalized epiandrosterone and [60]fullerene. Since a new stereocenter is created in the formation of the Prato monoaduct, two different diastereomers were isolated by HPLC (4, 5) whose absolute configurations were assigned according to the highly reliable "sector rule" on fullerenes. A further reaction of the malonate-containing diastereomer 5 with a second C60 molecule has afforded dumbbell fullerene 6 in which the two fullerene units are covalently connected through an epiandrosterone moiety. The new compounds have been spectroscopically characterized and their redox potentials, determined by cyclic voltametry, reveal three reversible reduction waves for hybrids 4 and 5, whereas these signals are split in dumbbell 6. Theoretical calculations at semiempirical (AM1) and single point B3LYP/6-31G(d) levels have predicted the most stable conformations for the hybrid compounds (4-6), showing the importance of the chlorine atom on the D ring of the steroid. Furthermore, TDDFT calculations have allowed assignments of the experimentally determined circular dichroism (CD) of the [60]fullerene-steroid hybrids based on the sign and position of the Cotton effects, despite the exceptionally large systems under study.

Diastereoselective synthesis of C60/steroid conjugates.

The design and synthesis of fullerene-steroid hybrids by using Prato's 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.

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.

Catalytic stereodivergent functionalization of H2@C60.

A complete stereocontrol of 1,3-dipolar cycloaddition of N-metalated azomethine ylides onto endohedral fullerene H2@C60 is reported for the first time. The stereodivergent synthesis of either the cis or the trans endohedral cycloadduct is achieved with excellent diastereo- and enantioselectivities.

Anefficient approach to chiral fullerene derivatives by catalytic enantioselective 1,3-dipolar cycloadditions.

Fullerene chirality is an important but undeveloped issue of paramount interest in fields such as materials science and medicinal chemistry. So far, enantiopure fullerene derivatives have been made from chiral starting materials or obtained by separating racemic mixtures. Here, we report the enantioselective catalytic synthesis of chiral pyrrolidinofullerenes (the most widely studied fullerene derivatives), which proceeds in high yields under very mild conditions at low temperatures. The combination of a particular metal catalyst-Ag(I) or Cu(II)-and a chiral ligand is able to direct the cycloaddition of buckminsterfullerene C(60), the first non-coordinating dipolarophile used in such reactions, to opposite enantiofaces of N-metallated azomethine ylides. This methodology has proven to be quite general, affording enantiomeric excesses of greater than 90%. Furthermore, well-defined chiral carbon atoms linked to the fullerene sphere are able to perturb the inherent symmetry of the fullerene π-system as revealed by circular dichroism measurements.