Stereoselectivity Nazarov cyclization

Si-directed Nazarov cyclization (14,164-165). Denmark etal.2 have examined the stereoselectivity of this cyclization with optically active P -silyldivinyl ketones... 

It is now well established that the Nazarov cyclization is a pericyclic reaction belonging to the class of electrocyclizations. As with all pericyclic reactions, mectuuiism and stereochemistry are inexorably coupled and any discussion of one feature must invoke the other. In this section the stereospecific aspects of the Nazarov cyclization are discussed, the stereoselective aspects of the reaction are dealt with individually in each of the following sections. 

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. 

Si-directed Nazarov cyclization This reaction proceeds with satisfactory stereoselectivity in the case of cyclohexenyl systems only cis ring-fused products 1 and 2 are formed. The stereoselectivity is significantly influenced by the bulk of the R group in the six-membered ring (equation I). 

The stereoselective synthesis of (+)-trichodiene was accomplished by K.E. Harding and co-workers. The synthesis of this natural product posed a challenge, since it contains two adjacent quaternary stereocenters. For this reason, they chose a stereospecific electrocyclic reaction, the Nazarov cyclization, as the key ring-forming step to control the stereochemistry. The cyclization precursor was prepared by the Friedel-Crafts acylation of 1,4-dimethyl-1-cyclohexene with the appropriate acid chloride using SnCU as the catalyst. The Nazarov cyclization was not efficient under protic acid catalysis (e.g., TFA), but in the presence of excess boron trifluoride etherate high yield of the cyclized products was obtained. It is important to note that the mildness of the reaction conditions accounts for the fact that both of the products had an intact stereocenter at C2. Under harsher conditions, the formation of the C2-C3 enone was also observed. 

Recently, an application of the silicon-directed Nazarov cyclization was reported in the stereoselective synthesis of (+ )-pentalene 29. The construction of the angularly fused cyclopentene ring is accomplished in 60% yield via the Nazarov cyclization. 

A Nazarov cyclization of the enone 151 was used to synthesize analogs of yuehchukene. The cyclization reaction proceeds in 83% yield. After reduction of the corresponding carbinol, reaction with indole in the presence of BF, introduces the indolyl substituent with trans stereoselectivity. <94SC65>... 

Nie J, Zhu HW, Cui HF, Hua MQ, Ma JA. Catalytic stereoselective synthesis of highly substituted indanones via tandem Nazarov cyclization and electrophilic fluorination trapping. Org. Lett. 2007 9 3053-3056. 

Recent applications of the Nazarov reaction, the cyclization of a 3-hydroxyphenyl-penta-l,4-dienyl cation, were reviewed.142 Tandem processes and asymmetric cycliza-tions were a particular focus of attention. Irradiation of (40) in aqueous base results in regioselective and stereoselective formation of (42).143 The allylic cation (41) is proposed as the key intermediate. A computational investigation was performed into the cofacial intermolecular n-n orbital interaction between n-conjugated main chains (C H +2) and allylic cations C3H54".144... 

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