Ene reaction

In organic chemistry, the ene reaction (also known as the Alder-ene reaction by its discoverer Kurt Alder in 1943) is a chemical reaction between an alkene with an allylic hydrogen (the ene) and a compound containing a multiple bond (the enophile), in order to form a new σ-bond with migration of the ene double bond and 1,5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the allylic position.

center|200px|Figure 1 - the ene reaction

This transformation is a group transfer pericyclic reaction, and therefore, usually requires highly activated substrates and/or high temperatures. Nonetheless, the reaction is compatible with a wide variety of functional groups that can be appended to the ene and enophile moieties. Many useful Lewis acid-catalyzed ene reactions have been also developed, which can afford high yields and selectivities at significantly lower temperatures.

Ene component

Enes are π-bonded molecules that contain at least one hydrogen atom at the allylic, propargylic, or α-position. Possible ene components include olefinic, acetylenic, allenic, aromatic, cyclopropyl, and carbon-hetero bonds. Usually, the allylic hydrogen of allenic components participates in ene reactions, but in the case of allenyl silanes, the allenic hydrogen atom α to the silicon substituent is the one transferred, affording a silylalkyne. Phenol can act as an ene component, for example in the reaction with dihydropyran, but high temperatures are required (); nevertheless, strained enes and fused small ring systems undergo ene reactions at much lower temperatures. Similarly, ene reactions with enols or enolates are classified as Conia-ene and Conia-ene-type reactions. In addition, ene components containing C=O, C=N and C=S bonds have been reported, but such cases are rare.

Enophile

Enophiles are typically electrophilic olefins. They are dienophiles. A range of π-bonded molecules with electron-withdrawing substituents also participate. In addition to carbon-carbon multiple bonds (olefins, acetylenes), enophiles may contain carbon-hetero multiple bonds (C=O in the case of carbonyl-ene reactions, C=N, C=S, ), hetero-hetero multiple bonds (N=N, O=O, Si=Si, N=O, S=O), cumulene systems (N=S=O, N=S=N, N=Se=N, C=C=O, C=C=S, ) and charged π systems (, , , ). Similarly, propargylic diazenes decompose readily through a retro-ene mechanism to give allene products and nitrogen gas (see Myers allene synthesis).

Mechanism

Uncatalyzed reaction

frame|center|Orbital interactions relevant to the concerted mechanism for the ene reaction

The HOMO of the ene and the LUMO of the enophile comprise the main frontier-orbital interaction in an ene reaction. The HOMO of the ene results from the combination of the pi-bonding orbital in the vinyl moiety and the allylic C-H bond. Concerted, all-carbon-ene reactions have, in general, a high activation barrier. A barrier of is calculated in the case of the propylene + ethylene. However, if the enophile becomes more polar (going from ethane to formaldehyde), its LUMO has a larger amplitude on C, yielding a better C–C overlap and a worse H–O one, determining the reaction to proceed in an asynchronous fashion. This translates into a lowering of the activation barrier until , if S replaces O on the enophile. By computationally examining both the activation barriers and the activation strains of several different ene reactions involving propene as the ene component, Fernandez and co-workers and the reaction can be designated as in the Woodward-Hoffmann notation.

DFT calculations, at the support a concerted mechanism. The development of 1,3-transannular interactions in the disfavored transition state provides a good explanation for the selectivity of this process.

frame|center|DFT study (B1B95/6-31G*) of a thermal intramolecular carbonyl–ene reaction and its use in the synthesis of jatropha-5,12-dienes

Catalyzed ene reactions

Computational work on aluminum-catalyzed glyoxylate-ene processes focus on a chair-like conformation at the transition state.

center|400px|Production of isoprene from isobutylene via ene reaction.

Regioselection

Just as in the case of any cycloaddition, the success of an ene reaction is largely determined by the steric accessibility of the ene allylic hydrogen. In general, methyl and methylene H atoms are abstracted much more easily than methine hydrogens. In thermal ene reactions, the order of reactivity for the abstracted H atom is primary> secondary> tertiary, irrespective of the thermodynamic stability of the internal olefin product. In Lewis-acid promoted reactions, the pair enophile/Lewis acid employed determines largely the relative ease of abstraction of methyl vs. methylene hydrogens. The high regio- and stereoselectivities that can be obtained in these reactions can offer considerable control in the synthesis of intricate ring systems.

Considering the position of attachment of the tether connecting the ene and enophile, Oppolzer

frame|center|Figure 12: Asymmetric glyoxylate-ene reaction catalyzed by a chiral titanium complex

As shown in Figure 13, Corey and co-workers propose an early transition state for this reaction, with the goal of explaining the high enantioselectivity observed (assuming that the reaction is exothermic as calculated from standard bond energies). Even if the structure of the active catalyst is not known, Corey's model proposes the following: the aldehyde is activated by complexation with the chiral catalyst by the formyl lone electron pair syn to the formyl hydrogen to form a pentacoordinate Ti structure. CH—O hydrogen bonding occurs to the stereoelectronically most favorable oxygen lone pair of the BINOL ligand. In such a structure, the top (re) face of the formyl group is much more accessible to a nucleophile attack, as the bottom (si) face is shielded by the neighboring naphthol moiety, thus affording the observed configuration of the product.

frame|center |Figure 13. Transition state proposed for the reaction in Figure 12.

The formal total synthesis of laulimalide (Figure 14) illustrates the robustness of the reaction developed by Mikami. Laulimalide is a marine natural product, a metabolite of various sponges that could find a potential use as an anti-tumor agent, due to its ability to stabilize microtubuli. One of the key steps in the strategy used for the synthesis of the C3-C16 fragment was a chirally catalyzed ene reaction that installed the C15 stereocenter. Treatment of the terminal allyl group of compound 1 with ethyl glyoxylate in the presence of catalytic provided the required alcohol in 74% yield and >95% ds. This method eliminated the need for a protecting group or any other functionality at the end of the molecule. In addition, by carrying out this reaction, Pitts et al. managed to avoid the harsh conditions and low yields associated with installing exo-methylene units late in the synthesis.

frame|center|Figure 14: Retrosynthetic analysis of the C3-C16 fragment of laulimalide and use of the ene reaction in its synthesis

Chiral C2-symmetric Cu(II) complexes and the synthesis of (+)-azaspiracid-1

Evans and co-workers have devised a new type of enantioselective C2-symmetric Cu(II) catalysts to which substrates can chelate through two carbonyl groups. The catalysts were found to afford high levels of asymmetric induction in several processes, including the ene reaction of ethyl glyoxylate with different unactivated olefins. Figure 15 reveals the three catalysts they found to be the most effective in affording gamma-delta-unsaturated alpha-hydroxy esters in high yields and excellent enantio-selectivities. What is special about compound 2 is that it is bench-stable and can be stored indefinitely, making it convenient to use. The reaction has a wide scope, as shown in Figure 16, owing to the high Lewis acidity of the catalysts, which can activate even weakly nucleophilic olefins, such as 1-hexene and cyclohexene.

frame|center| Figure 15. C2-symmetric Cu(II) catalysts developed for the enantioselective carbonyl-ene reactions of olefins and ethyl glyoxylate

frame|center| Figure 16. Scope of the reaction catalyzed by C2-symmetric Cu(II) chiral Lewis acids

In the case of catalysts 1 and 2, it has been proposed that asymmetric induction by the catalysts results from the formation of a square-planar catalyst-glyoxylate complex (Figure 17), in which the Re face of the aldehyde is blocked by the tert-butyl substituents, thus allowing incoming olefins to attack only the Si face. This model does not account however for the induction observed when catalyst 3 was employed. The current view is that the geometry of the metal center becomes tetrahedral, such that the sterically shielded face of the aldehyde moiety is the Re face.

frame|center| Figure 17. Square planar and tetrahedral Cu (II) stereochemical models.

Initially, the value of the method developed by Evans and coworkers was proved by successfully converting the resulting alpha-hydroxy ester into the corresponding methyl ester, free acid, Weinreb amide and alpha-azido ester, without any racemization, as shown in Figure 18. The azide displacement of the alcohol that results from the carbonyl ene reaction provides a facile route towards the synthesis of orthogonally protected amino acids.

frame|center|Figure 19: Structure of (+)-azaspiracid-1 and the ene reaction used to introduce the C17 stereocenter