Nazarov cyclization reaction

The Nazarov cyclization reaction (often referred to as simply the Nazarov cyclization) is a

As originally described, the Nazarov cyclization involves the activation of a

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.^{[2][3][4][5][6][7]}

Mechanism

The mechanism of the classical Nazarov cyclization reaction was first demonstrated experimentally by

As noted above, variants that deviate from this template are known; what designates a Nazarov cyclization in particular is the generation of the pentadienyl

Similarly, β-substitution directed inward restricts the s-trans conformation so severely that

Along this same vein, allenyl vinyl ketones of the type studied extensively by Marcus Tius of the

Classical Nazarov cyclizations

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

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

Shortcomings

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.^[2]

1. Strong Lewis or protic acids are typically required for the reaction (e.g.
   BF₃, MeSO₃H
   ). These promoters are not compatible with sensitive functional groups, limiting the substrate scope.
2. Despite the mechanistic possibility for catalysis, multiple equivalents of the promoter are often required in order to effect the reaction. This limits the atom economy of the reaction.
3. The elimination step is not
   regioselective; if multiple β-hydrogens are available for elimination, various products are often observed as mixtures. This is highly undesirable from an efficiency standpoint as arduous separation
   is typically required.
4. Elimination destroys a potential stereocenter, decreasing the potential usefulness of the reaction.
5. Protonation of the enolate is sometimes not
   stereoselective, meaning that products can be formed as mixtures of epimers
   .

Modern variants

The shortcomings noted above limit the usefulness of the Nazarov cyclization reaction in its canonical form. However, modifications to the reaction focused on remedying its issues continue to be an active area of

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.^[10]

Polarization

Drawing on the substituent effects compiled over various trials of the reaction, Professor Alison Frontier of the

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.

Alternative cation generation

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.^[2] One such example involves the silver catalyzed cationic ring opening of allylic dichloro cylopropanes. The silver salt facilitates loss of chloride via precipitation of insoluble silver chloride.^[15]

In the

Interrupted cyclization

Once the cyclization has occurred, an oxyallyl cation is formed. As discussed extensively above, the typical course for this intermediate is

Enolate trapping with various

Enantioselective variants

The development of an

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

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.^[2]

Tius has additionally developed a

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.^[2]

Related Reactions

Extensions of the Nazarov cyclization are generally also subsumed under the same name. For example, an α-β, γ-δ unsaturated

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.[2]

Imino-Nazarov reaction

Nitrogen analogues of the Nazarov cyclization reaction (known as imino-Nazarov cyclization reactions) have few instances; there is one example of a generalized imino-Nazarov cyclization reported (shown below),^[24] and several iso-imino-Nazarov reactions in the literature.^[25][26] 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.^[27]

See also

References