Abel de Cózar

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

Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes.

Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results.

An Amine-Catalyzed Enantioselective [3+2] Cycloaddition of Azomethine Ylides and α,β-Unsaturated Aldehydes: Applications and Mechanistic Implications

The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and α,β-unsaturated aldehydes catalyzed by α,α-diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2-alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5-alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway.

Stereocontrolled (3+2) cycloadditions between azomethine ylides and dipolarophiles: a fruitful interplay between theory and experiment

In this article we present recent developments in (3+2) cycloadditions with special emphasis on 1,3-dipolar reactions involving azomethine ylides and alkenes possessing electron withdrawing groups. It is found that there is not a general mechanism for these reactions since both concerted aromatic [(π)4(s)+(π)2(s)] mechanisms and stepwise processes involving zwitterionic intermediates can be found. These computational models can be extended to analyse the role of chiral catalysts in these reactions in order to understand the nature of the catalytic cycle and the origins of chiral induction.

Concerted and Stepwise Mechanisms in Metal-Free and Metal-Assisted [4 + 3] Cycloadditions Involving Allyl Cations

The thermal [4+3] cycloaddition reaction between allenes and tethered dienes (1,3-butadiene and furan) assisted by transition metals (Au(I), Au(III), Pd(II), and Pt(II)) was studied computationally within the density functional theory framework and compared to the analogous non-organometallic process in terms of activation barriers, synchronicity and aromaticity of the corresponding transition states. It was found that the metal-mediated cycloaddition reaction is concerted and takes place via transition structures that can be even more synchronous and more aromatic than their non-organometallic analogues. However, the processes exhibit slightly to moderately higher activation barriers than the parent cycloaddition involving the hydroxyallylic cation. The bond polarization induced by the metal moiety is clearly related to the interaction of the transition metal with the allylic π* molecular orbital, which constitutes the LUMO of the initial reactant. Finally, replacement of the 1,3-butadiene by furan caused the transformation to occur stepwise in both the non-organometallic and metal-assisted processes.

Densely substituted unnatural L- and D-prolines as catalysts for highly enantioselective stereodivergent (3 + 2) cycloadditions and aldol reactions

(3 + 2) Cycloaddition reaction between azomethine ylides and π-deficient alkenes leads to densely substituted L- and D-unnatural prolines. These (3 + 2) cycloadducts in turn catalyse the preparation of an offspring of unnatural endo- and exo-L-proline derivatives. These latter compounds are also efficient catalysts of aldol reactions and yield aldol adducts with the opposite stereochemistry obtained under natural L-Pro organocatalysis.

Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

Summary The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and gold(I) catalysts in this reaction was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield. The origin of the enantioselectivity of the chiral gold(I) catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.

Enantioselective Synthesis of Polysubstituted Spiro-nitroprolinates Mediated by a (R,R)-Me-DuPhos·AgF-Catalyzed 1,3-Dipolar Cycloaddition

The synthesis of constrained spirocycles is achieved effectively by means of 1,3-dipolar cyclodditions employing α-imino γ-lactones as azomethine ylide precursors and nitroalkenes as dipolarophiles. The complex formed by (R,R)-Me-DuPhos 18 and AgF is the most efficient bifunctional catalyst. Final spiro-nitroprolinates cycloadducts are obtained in good to moderate yields and both high diastereo- and enantioselectivities. Density functional theory (DFT) calculations supported the expected absolute configuration as well as other stereochemical parameters.

Alkenyl Arenes as Dipolarophiles in Catalytic Asymmetric 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides

The use of alkenyl arenes as dipolarophiles in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides is reported. Under appropriate reaction conditions with a CuI or AgI catalyst either the exo or the endo adduct was obtained with high stereoselectivity. This process provides efficient access to highly enantiomerically enriched 4-aryl proline derivatives. The observed results are compatible with the blockage of one prochiral face of the 1,3-dipole, as well as with the efficient transmission of electrophilicity towards the terminal carbon atom of the dipolarophile. This polarization results in a change from a concerted to a stepwise mechanism.