page_title: Ene reaction
section_title: Chiral C2-symmetric Cu(II) complexes and the synthesis of (+)-azaspiracid-1
hierarchical_section_title: Ene reaction / Chiral Lewis acids for the asymmetric catalysis of carbonyl-ene reactions / Chiral C2-symmetric Cu(II) complexes and the synthesis of (+)-azaspiracid-1
caption_attribution_description: English: fig 15
context_page_description: The ene reaction is a chemical reaction between an alkene with an allylic hydrogen and a compound containing a multiple bond, 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.
  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, making the ene reaction a useful C–C forming tool for the synthesis of complex molecules and natural products.
context_section_description: 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.
  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.
  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.
  The synthetic utility of the chiral C2-symmetric Cu(II) catalysts was truly revealed in the formation of the C17 stereocenter of the CD ring fragment of (+)-azaspiracid-1, a very potent toxin (cytotoxic to mammalian cells) produced in minute quantities by multiple shellfish species including mussels, oysters, scallops, clams, and cockles. As shown in Figure 19, the reaction that establishes the C17 stereocenter is catalyzed by 1 mol % Cu(II) complex 2 (Figure 15), and the authors note that it can be conducted on a 20 g scale and still give very good yields and excellent enantioselectivities. Furthermore, the product can be easily converted into the corresponding Weinreb amide, without any loss of selectivity, allowing for the facile introduction of the C14 methyl group. Thus, this novel catalytic enantioselective process developed by Evans and coworkers can be easily integrated into complex synthesis projects, particularly early on in the synthesis, when high yields and enantioselectivites are of utmost importance.
caption: Figure 15. C2-symmetric Cu(II) catalysts developed for the enantioselective carbonyl-ene reactions of olefins and ethyl glyoxylate
exif: {}