page_title: Nazarov cyclization reaction
section_title: Enantioselective variants
hierarchical_section_title: Nazarov cyclization reaction / Modern variants / Enantioselective variants
caption_attribution_description: English: lewis acid mediated asymmetric nazarov cyclization
context_page_description: The Nazarov cyclization reaction is a chemical reaction used in organic chemistry for the synthesis of cyclopentenones. The reaction is typically divided into classical and modern variants, depending on the reagents and substrates employed. It was originally discovered by Ivan Nikolaevich Nazarov in 1941 while studying the rearrangements of allyl vinyl ketones.
  As originally described, the Nazarov cyclization involves the activation of a divinyl ketone using a stoichiometric Lewis acid or protic acid promoter. The key step of the reaction mechanism involves a cationic 4π-electrocyclic ring closure which forms the cyclopentenone product. As the reaction has been developed, variants involving substrates other than divinyl ketones and promoters other than Lewis acids have been subsumed under the name Nazarov cyclization provided that they follow a similar mechanistic pathway.
  The success of the Nazarov cyclization as a tool in organic synthesis stems from the utility and ubiquity of cyclopentenones as both motifs in natural products and as useful synthetic intermediates for total synthesis. The reaction has been used in several total syntheses and several reviews have been published.
context_section_description: The development of an enantioselective Nazarov cyclization is a desirable addition to the repertoire of Nazarov cyclization reactions. To that end, several variations have been developed utilizing chiral auxiliaries and chiral catalysts. Diastereoselective cyclizations are also known, in which extant stereocenters direct the cyclization. Almost all of the attempts are based on the idea of torquoselectivity; selecting one direction for the vinyl groups to "rotate" in turn sets the stereochemistry as shown below.
  Silicon-directed Nazarov cyclizations can exhibit induced diastereoselectivity in this way. In the example below, the silyl-group acts to direct the cyclization by preventing the distant alkene from rotating "towards" it via unfavorable steric interaction. In this way the silicon acts as a traceless auxiliary. (The starting material is not enantiopure but the retention of enantiomeric excess suggests that the auxiliary directs the cyclization.)
  Tius's allenyl substrates can exhibit axial to tetrahedral chirality transfer if enantiopure allenes are used. The example below generates a chiral diosphenpol in 64% yield and 95% enantiomeric excess.
  Tius has additionally developed a camphor-based auxiliary for achiral allenes that was employed in the first asymmetric synthesis of roseophilin. The key step employs an unusual mixture of hexafluoro-2-propanol and trifluoroethanol as solvent.
  The first chiral Lewis acid promoted asymmetric Nazarov cyclization was reported by Varinder Aggarwal and utilized copper (II) bisoxazoline ligand complexes with up to 98% ee. The enantiomeric excess was unaffected by use of 50 mol% of the copper complex but the yield was significantly decreased.
caption: Lewis-acid mediated asymmetric Nazarov cyclization
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