Fernando P. Cossío

The mechanism of the ketene-imine (staudinger) reaction in its centennial: still an unsolved problem?

[Reaction: see text]. Although Staudinger reported the reaction between ketenes and imines 100 years ago (1907), this process is still the most general and useful method for the synthesis of beta-lactams and their derivatives. This reaction is a [2 + 2] thermal cycloaddition in which two chiral centers may be generated in one preparative step. Staudinger reactions involving alpha,beta-unsaturated imines or ketenes have issues concerning the [2 + 2] or [4 + 2] periselectivity of the reaction. This Account discusses how the main factors that determine the regiochemical and stereochemical outcomes of this reaction were elucidated with computational and experimental data. This fruitful interplay between theory and experiment has revealed that the [2 + 2] cycloaddition is actually a two-step process. The first step is a nucleophilic addition of the nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene. This attack forms a zwitterionic intermediate that evolves toward the final beta-lactam cycloadduct. The second step can be viewed as a four-electron conrotatory electrocyclization that is subject to torquoelectronic effects. When alpha,beta-unsaturated imines are used, the zwitterionic intermediates yield either the corresponding 4-vinyl-beta-lactams or the alternative 3,4-dihydropyridin-2(1 H)-ones. In this latter case, the cyclization step consists of a thermal disrotatory electrocyclization. In the context of stereoselectivity, it is usually assumed that the first step takes place through the less hindered side of the ketene. The cis-trans selectivity of the reaction depends on the geometry of the imine. As the general rule, ( E)-imines form cis-beta-lactams whereas ( Z)-imines yield trans-beta-lactams. Most of the experimental results point to the two-step model. The asymmetric torquoselectivity of the conrotatory ring closure of the second step accounts for the stereochemical discrimination in the reaction of chiral ketenes or chiral imines. Nevertheless, recent studies have revealed that isomerization paths in the imine or in the zwitterion may determine the stereochemistry of the reaction. Thus, if the rotation about the N1-C4 bond of the zwitterion intermediate is faster than the cyclization, the formation of trans-beta-lactams from ( E)-imines is biased. Alternatively, in some cases, the ( E)-( Z) isomerization of the starting imines prior to the cycloaddition steps also results in the formation of trans-cycloadducts. Although the main variables that govern the outcome of the reaction have been elucidated, there are still several aspects of the reaction yet to be disclosed. Finally, the discovery of the catalytic version of the reaction is a new and formidable mechanistic challenge and will be a nice playground for forthcoming theoretical-experimental discussions.

Dyotropic Reactions: Mechanisms and Synthetic Applications†

In 1972, M. T. Reetz defined dyotropic (from the greek dyo, meaning two) rearrangements as a new class of pericyclic valence isomerizations in which two σ-bonds simultaneously migrate intramolecularly.1,2 Reactions in which the two migrating groups interchange their relative positions were designated as type I (Scheme 1A) whereas those of type II involve migration to new bonding sites without positional interchange (Scheme 1B,C). The uncatalyzed and concerted nature of these processes was also proposed.3,4 Nowadays, dyotropic transformations are standard tools for the construction of organic and organometallic molecules. Frequently, this unique rearrangement is the single entry to an efficient preparation of target molecules. Moreover, the discovery of new dyotropic reactions involving transition metals and excited states had widened the mechanistic scope of these processes to new reaction pathways well away from the original definition of uncatalyzed and concerted processes. This review comprehensively reports the dyotropic reactions studied since the seventies, accounts for the different reaction mechanisms for these rearrangements, and discusses their synthetic applications in organic and organometallic chemistry.

Highly stereoselective synthesis of α-hydroxy β-amino acids through β-lactams: application to the synthesis of the taxol and bestatin side chains and related systems.

Abstract Formation of α-hydroxy β-lactams, followed chemical elaboration at C 4 and further βlactam cleavage afforded functionalised α-hydroxy β-amino acids or their derivatives in a highly stereoselective manner.

Aromaticity and Activation Strain Analysis of [3 + 2] Cycloaddition Reactions between Group 14 Heteroallenes and Triple Bonds

We have computationally explored the trend in reactivity of [3 + 2] cycloaddition reactions between H(2)E=C=PH and HC≡CH as the terminal position in the phosphaallene is varied along E = C, Si, Ge, Sn, Pb. The reaction barrier drops significantly from E = C (nearly 50 kcal/mol) to E = Si-Pb (ca. 20 kcal/mol). Activation strain analyses tie this trend to a reduction in activation strain in the heavier phosphaallene analogues which, in contrast to the parent compound H(2)C=C=PH, do already possess the bent geometry required in the TS.

Monomer versus Alcohol Activation in the 4-Dimethylaminopyridine-Catalyzed Ring-Opening Polymerization of Lactide and Lactic O-Carboxylic Anhydride

Model reactions for the 4-dimethylaminopyridine (DMAP)-catalyzed ring-opening polymerization of lactide and the corresponding lactic O-carboxylic anhydride (lacOCA) have been studied computationally at the B3LYP/6-31G(d) level of theory. The solvent effect of dichloromethane was taken into account through PCM/SCRF single-point calculations at the B3LYP/6-31G(d) level of theory. In marked contrast with that predicted for the reaction of alcohols with acetic anhydride, the mechanism in which nucleophilic activation of the monomer involving acylpyridinium intermediates was found to be energetically less favorable than the base activation of the alcohol through hydrogen bonding. The concerted pathway for the ring-opening of lactide and lacOCA was shown to compete with the traditional stepwise mechanism involving tetrahedral intermediates. Furthermore, DMAP is proposed to act as a bifunctional catalyst through its basic nitrogen center and an acidic ortho-hydrogen atom.

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.

Double Group Transfer Reactions: Role of Activation Strain and Aromaticity in Reaction Barriers

Double group transfer (DGT) reactions, such as the bimolecular automerization of ethane plus ethene, are known to have high reaction barriers despite the fact that their cyclic transition states have a pronounced in-plane aromatic character, as indicated by NMR spectroscopic parameters. To arrive at a way of understanding this somewhat paradoxical and incompletely understood phenomenon of high-energy aromatic transition states, we have explored six archetypal DGT reactions using density functional theory (DFT) at the OLYP/TZ2P level. The main trends in reactivity are rationalized using the activation strain model of chemical reactivity. In this model, the shape of the reaction profile DeltaE(zeta) and the height of the overall reaction barrier DeltaE( not equal)=DeltaE(zeta=zeta(TS)) is interpreted in terms of the strain energy DeltaE(strain)(zeta) associated with deforming the reactants along the reaction coordinate zeta plus the interaction energy DeltaE(int)(zeta) between these deformed reactants: DeltaE(zeta)=DeltaE(strain)(zeta)+DeltaE(int)(zeta). We also use an alternative fragmentation and a valence bond model for analyzing the character of the transition states.

Type-I Dyotropic Reactions: Understanding Trends in Barriers

To understand the factors that control the activation barrier of type-I 1,2-dyotropic reactions (X-EH(2)-CH(2)-X*→X*-EH(2)-CH(2)-X, with E=C and Si, X=H, CH(3), SiH(3), F to I) and trends therein as a function of the migrating groups X, we have explored ten archetypal model reactions of this class using relativistic density functional theory (DFT) at ZORA-OLYP/TZ2P. The main trends in reactivity are rationalized using the activation strain model of chemical reactivity, which had to be extended from bimolecular to unimolecular reactions. Thus, the above type-I dyotropic reactions can be conceived as a relative rotation of the CH(2)CH(2) and [X···X] fragments in X-CH(2)-CH(2)-X. The picture that emerges from these analyses is that reduced C-X bonding in the transition state is the origin of the reaction barrier. Also the trends in reactivity on variation of X can be understood in terms of how sensitive the C-X interaction is towards adopting the transition-state geometry. A valence bond analysis complements the analyses and confirms the picture emerging from the activation strain model.

Efficient tautomerization hydrazone-azomethine imine under microwave irradiation. Synthesis of [4,3′] and [5,3′]bipyrazoles

Abstract Microwave irradiation induces the thermal isomerization of pyrazolyl hydrazones to the corresponding azomethine imines which undergo 1,3-dipolar cycloaddition with electron-poor dipolarophiles in a few min with good yields. By classical heating, several dipolarophiles do not react in comparable reaction conditions. Regiochemistry of bipyrazoles obtained from unsymmetrical dipolarophiles has been inferred by spectroscopic experiments.

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