Nazarov cyclization reaction
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.
Activation of the ketone by the acid catalyst generates a pentadienyl cation, which undergoes a thermally allowed 4π conrotatory electrocyclization as dictated by the Woodward-Hoffman rules.
[2] Similarly, β-substitution directed inward restricts the s-trans conformation so severely that E-Z isomerization has been shown to occur in advance of cyclization on a wide range of substrates, yielding the trans cyclopentenone regardless of initial configuration.
[2] (See Interrupted cyclizations below) Along this same vein, allenyl vinyl ketones of the type studied extensively by Marcus Tius of the University of Hawaii show dramatic rate acceleration due to the removal of β-hydrogens, obviating a large amount of steric strain in the s-cis conformer.
[6] Though cyclizations following the general template above had been observed prior to Nazarov's involvement, it was his study of the rearrangements of allyl vinyl ketones that marked the first major examination of this process.
Nazarov correctly reasoned that the allylic olefin isomerized in situ to form a divinyl ketone before ring closure to the cyclopentenone product.
[10] Research involving the reaction was relatively quiet in subsequent years, until in the mid-1980s when several syntheses employing the Nazarov cyclization were published.
Shown below are key steps in the syntheses of Trichodiene and Nor-Sterepolide, the latter of which is thought to proceed via an unusual alkyne-allene isomerization that generates the divinyl ketone.
The first two are not evident from the mechanism alone, but are indicative of the barriers to cyclization; the last three stem from selectivity issues relating to elimination and protonation of the intermediate.
The earliest efforts to improve the selectivity of the Nazarov cyclization took advantage of the β-silicon effect in order to direct the regioselectivity of the elimination step.
This chemistry was developed most extensively by Professor Scott Denmark of the University of Illinois, Urbana-Champaign in the mid-1980s and utilizes stoichiometric amounts of iron trichloride to promote the reaction.
The cyclization takes place before elimination of the benzyl alcohol moiety, so that the resulting stereochemistry of the newly formed ring arises from approach of the silyl alkene anti to the ether.
In one study, the Nazarov cyclization is paired with a Michael reaction using an iridium catalyst to initiate nucleophilic conjugate addition of the enolate to β-nitrostyrene.
In this tandem reaction the iridium catalyst is required for both conversions: it acts as the Lewis acid in the Nazarov cyclization and in the next step the nitro group of nitrostyrene first coordinates to iridium in a ligand exchange with the carbonyl ester oxygen atom before the actual Michael addition takes place to the opposite face of the R-group.
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.
[2][20] 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.
