Stereoselective Nazarov reaction

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... 

In 1998, the first deliberate attempt to trap the oxyallyl cation with a nucleophile during a thermal Nazarov reaction was reported by West and coworkers [23]. Coining the term interrupted Nazarov reaction, they described the interception of the oxyallyl intermediate of a Nazarov reaction by a tethered alkene (Scheme 3.20). Upon submission of divinyl ketones 87 to the LA, a conrotatory ring closure generates the oxyallyl cation intermediate 89. The alkene moiety adds selectively to the oxyallyl cation intermediate to form bicycle 90. The stabilized tertiary carbocation is then trapped by the enolate oxygen to give intermediate 91, which, under acidic aqueous conditions, is converted to the final hemiketal product 88. The reaction provides an efficient and stereoselective method to prepare tricychc compounds 88 in yields ranging from 42 to 89% [24]. 

Scheme 3.20 Stereoselective interrupted Nazarov reaction and trapping of the oxyallyl cation intermediate...

Si-directed Nazarov cyclization2 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). 

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. 

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. 

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>... 

A similar reaction was also reported by Jprgensen s group regarding the addition of Nazarov reagents (75) to enals (15). The reaction furnishes highly substituted cyclohexanones in high yields and stereoselectivities via an organocatalytic tandem Michael/Morita-Baylis-Hillman reaction catalyzed by the diphenylprolinol derivative VII [50]. 

Combining this cycloisomerization reaction with met-aUa-Nazarov rearrangement gave tetracyclic cyclopropanes 334 in good yield. The stereoselectivity was very high, and a single isomer was isolated (Scheme 1.161) [231]. 

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