Tautomerization Nazarov cyclization

Nazarov processes have allowed access to intermediate cyclic enolates . Enone 134 undergoes a Nazarov cyclization catalysed by a Lewis acid [e.g. Cu(OTf)2] to give the intermediate enol complex 135, which undergoes tautomerization to the diastereoiso-merically pure cyclic enone trans-136 in almost quatitative yield (equation 35)445,446... 

Beyond the disrotatory or conrotatory stereochemical imperative which must accompany all Nazarov cyclizations there exists a secondary stereochemical feature. This feature arises because of the duality of allowed electrocyclization pathways. When the divinyl ketone is chiral the two pathways lead to dia-stereomers. The nature of the relationship between the newly created centers and preexisting centers depends upon the location of the cyclopentenone double bond. The placement of this double bond is established after the electrocyclization by proton loss from the cyclopentenyl cation (equation 5). Loss of H, H or in this instance generates three tautomeric products. The lack of control in this event is a drawback of the classical cyclization. Normally, the double bond occupies the most substituted position corresponding to a Saytzeff process. The issue of stereoselection with chiral divinyl ketones is iUustrated in Scheme 7. The sense of rotation is defined by clockwise (R) or counterclockwise (5) viewing down the C—O bond. Thus, depending on the placement of the double bond, the newly created center may be proximal or distal to the preexisting center. If = H the double bond must reside in a less substituted environment to establish stereoselectivity. 

Electrocyclic reactions are not limited to neutral polyenes. The cyclization of a pentadienyl cation to a cyclopentenyl cation offers a useful entry to five-membered carbocycUc compounds. One such reaction is the Nazarov cyclization of divinyl ketones. Protonation or Lewis acid complexation of the oxygen atom of the carbonyl group of a divinyl ketone generates a pentadienyl cation. This cation undergoes electrocyclization to give an allyl cation within a cyclopentane ring. The allyl cation can lose a proton or be trapped, for example by a nucleophile. Proton loss occurs to give the thermodynamically more stable alkene and subsequent keto-enol tautomerism leads to the typical Nazarov product, a cyclopentenone (3.220). 

Silicon-directed Nazarov cyclization Activation of the ketone 1 by a Lewis acid catalyst generates a pentadienyl cation, which undergoes a thermally allowed 4Tr-electron conrotatory electrocyclization (Scheme 2.19). This generates a silicon-stabilized cation, which undergoes an elimination reaction of silyl group to give the cyclopentadienol. Subsequent tautomerization of cyclopentadienol produces the cyclopentenone product 2. 

An imaginative approach to the cephalotaxine alkaloids was reported by Li and co-workers and used a functional equivalent of the Nazarov cyclization. Iron-mediated oxidation of substrate 120 gave intermediate 121. Tautomerization of 121 to 122 followed by electrocyclization gave annulated product 123. This key intermediate was subsequently converted into cephalotaxine (124). 

Following the suggestion of Braude and Coles, Nazarov established the role of the tautomeric divinyl ketones as the true precursors of cyclization. By conducting the cyclization of the allyl vinyl ketone (1) in D3PO4 it was established that one deuterium is introduced into Ae cyclic product (2 Scheme 9). Direct cyclization of the divinyl ketone (3) with D3PO4 gave identical resdts. ... 

The Nazarov reaction is a conrotatory [4rt]electrocychzation. Overall, the transformation involves conversion of a divinyl ketone 1 into a cyclopentenone 5 (Scheme 3.1). The reaction is triggered by complexation of the ketone with a Lewis acid (LA) or protonation, leading to the formation of the pentadienyl cation 2. This intermediate undergoes cyclization to yield the oxyallyl cation 3, which, after deprotonation, affords the cychc dienol 4, which tautomerizes to the final cyclopentenone 5. Owing to the frequent occurrence of five-membered carbocycles in natural products, the usefulness of the Nazarov reaction in total synthesis becomes evident. 

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See also in sourсe #XX -- [ ]

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