Nazarov cyclization reaction

Chemical reaction used in organic chemistry

The Nazarov cyclization reaction (often referred to as simply the Nazarov cyclization) 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 (1906–1957) 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 (See Mechanism below). 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 (including jasmone, the aflatoxins, and a subclass of prostaglandins) and as useful synthetic intermediates for total synthesis. The reaction has been used in several total syntheses and several reviews have been published.

The mechanism of the classical Nazarov cyclization reaction was first demonstrated experimentally by Charles Shoppee to be an intramolecular electrocyclization and is outlined below. 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. This generates an oxyallyl cation which undergoes an elimination reaction to lose a β hydrogen. Subsequent tautomerization of the enolate produces the cyclopentenone product. As noted above, variants that deviate from this template are known; what designates a Nazarov cyclization in particular is the generation of the pentadienyl cation followed by electrocyclic ring closure to an oxyallyl cation. In order to achieve this transformation, the molecule must be in the s trans/s trans conformation, placing the vinyl groups in an appropriate orientation. The propensity of the system to enter this conformation dramatically influences reaction rate, with α substituted substrates having an increased population of the requisite conformer due to allylic strain. Coordination of an electron donating α substituent by the catalyst can likewise increase the reaction rate by enforcing this conformation. 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 classical version of the Nazarov cyclization suffers from several drawbacks which modern variants attempt to circumvent. 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 silicon directed Nazarov cyclization reaction was subsequently employed in the synthesis of the natural product Silphinene, shown below. 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. It is often possible to achieve catalytic activation using a donating or withdrawing group alone, although the efficiency of the reaction (yield, reaction time, etc.) is typically lower.

By extension, any pentadienyl cation regardless of its origin is capable of undergoing a Nazarov cyclization. There have been a large number of examples published where the requisite cation is arrived at by a variety of rearrangements. In the total synthesis of rocaglamide, epoxidation of a vinyl alkoxyallenyl stannane likewise generates a pentadienyl cation via ring opening of the resultant epoxide.

Once the cyclization has occurred, an oxyallyl cation is formed. As discussed extensively above, the typical course for this intermediate is elimination followed by enolate tautomerization. However, these two steps can be interrupted by various nucleophiles and electrophiles, respectively. Oxyallyl cation trapping has been developed extensively by Fredrick G. West of the University of Alberta and his review covers the field. The oxyallyl cation can be trapped with heteroatom and carbon nucleophiles and can also undergo cationic cycloadditions with various tethered partners. Shown below is a cascade reaction in which successive cation trapping generates a pentacyclic core in one step with complete diastereoselectivity. Enolate trapping with various electrophiles is decidedly less common. 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.

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. 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. Other such extensions have been given similar names, including homo Nazarov cyclizations and vinylogous Nazarov cyclizations.

Because they overstabilize the pentadienyl cation, β electron donating substituents often severely impede Nazarov cyclization. Building from this, several electrocyclic ring openings of β alkoxy cyclopentanes have been reported. These are typically referred to as retro Nazarov cyclization reactions. and several iso imino Nazarov reactions in the literature. Even these tend to suffer from poor stereoselectivity, poor yields, or narrow scope. The difficulty stems from the relative over stabilization of the pentadienyl cation by electron donation, impeding cyclization.