Reductive Nazarov cyclization

Giese, S., West, F. G. The reductive Nazarov cyclization. Tetrahedron Lett. 1998, 39, 8393-8396. 

Since steric hindrance disfavours cyclization for substrates with internal P-substitution, double-bond isomerization is often a competing pathway. Indeed, West found that reductive Nazarov cyclizations (see Section 3.4.S.2) of either trans- or cw-disubstituted enones 49a or 49b, both produced a single diastereomeric product 50a. The stereochemistry of 50a corresponds to a conrotatory cyclization of trans-isomer 49a, thereby indicating that while the trans-isomer 49a cyclizes, the cw-isomer 49b first isomerizes before cyclization. Recent studies by Frontier and co-workers on polarized Nazarov cyclizations also found that in the case of alkylidene p ketoester substrates (for example, see 46), reaction rates depended on the competing rate of isomerization, which depended on the nature of the P-... 

A bis([2.2]paracyclophane)-annelated cyclopentadiene could be synthesized via a Nazarov cyclization of the bis([2.2]paracyclophane-l,9-dienyl) ketone 136 prepared by addition of monolithiodiene 133 to ethyl formate and subsequent oxidation of the carbinol 110. The synthesis was completed by diisobutylalumi-num hydride (DIBA1-H) reduction of the resulting cyclopentenone, and dehydration with p-toluenesulfonic acid. Treatment with methyllithium gave the corresponding cyclopentadienyllithium 136-Li, which was identified by NMR spec-... 

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>... 

The Nazarov cyclization is a four-electron cyclization and occurs thermally by a conrotatory process. The stereochemical outcome across the new carbon-carbon bond is often obscured by the loss of a proton at one of these centres during the cyclopentenone formation. If, however, the proton loss occurs exo to the five-membered ring or if the aUyl cation is quenched by a nucleophile, then the stereochemistry can be observed. For example, trapping the allyl cation by reduction with... 

One important development however, was the identification of a reductive trapping pathway, allowing the isolation of saturated cyclopentanones. Lewis acid promoted Nazarov cyclization of substrate 104, followed by reductive quenching by triethyl silane resulted in the formation of ketones 106 and enol silanes 107. Such a reaction process requires only 10 mol % of the Lewis acid promoter, with hydride addition occurring at the less-substituted position of the oxyallyl cation 105. Mixtures of compounds isomeric at the a-positions were isolated in these reactions due to the rapid epimerization of these centers during acidic workup. 

This isomerization process v rould not usually be detected, because the elimination step removes one of the stereocenters during most Nazarov reactions. Prior to Frontier s v rork. West and cov rorkers [8, 9] reported a reductive Nazarov cydization. Thus, v rhen both 23 and 25 v rere submitted to the reductive Nazarov conditions, only product 24 v ras observed (Scheme 3.7) supporting the isomerization/cyclization hypothesis. 

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