Asymmetric Nazarov cyclization

Nazarov, I. N. Torgov, I. B. Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I. N. Nazarov (1900-1957), a Soviet Union Scientist, discovered this reaction in 1942. It was said that almost as many young synthetic chemists have been lost in the pursuit of an asymmetric Nazarov cyclization as of the Bayliss-HiUman reaction. 

Perhaps the most elegant and attractive method to control absolute stereochemistry, however, is the use of asymmetric catalysis, and several examples of this approach have been applied to the Nazarov cyclization. Traimer and co-workers were the first to report a single example of a successfiil asymmetric Nazarov cyclization catalyzed by chiral scandium complex in 2003. In the exact same issue of the journal however, Aggarwal and co-workers reported a more in-depth study using copper pyBOX complexes. ... 

Scheme 8 Br0nsted-acid-catalyzed asymmetric Nazarov cyclization.

SCHEME 19.31. Pyranose-derived chiral auxiliaries for asymmetric Nazarov cyclization. 

Basak AK, Shimada N, Bow WE, Vicic DA, Tius MA. An organocatal)ftic asymmetric Nazarov cyclization. J. Am. Chem. Soc. 2010 132 8266-8267. 

Rueping M, leawsuwan W, Antonchick AP, Nachtsheim BJ. Chiral Brpnsted acids in the catalytic asymmetric Nazarov cyclization-the first enantioselective organocatalytic electrocyclic reaction. Angew. Chem. Int. Ed. 2007 46 2097-2100. 

During the last decade, asymmetric Nazarov cyclization was a focus of several research groups.Interestingly, in the course of the electrocylization process, the Nazarov reaction allows for access to a potent chiral enolate. 

SCHEME 31.44. Recent progress toward the asymmetric Nazarov cyclization involving an enantioselective protonation step. 

A Br0nsted acid-catalysed asymmetric Nazarov cyclization of acyclic a-alkoxy dienones to chiral cyclopentenones has been reported (Scheme 169). ... 

Rueping employed N-triflyl phosphoramide 13d in the Nazarov cydization to afford cis-cyclopentenones with moderate diasterselechvihes in excellent yields and ee s. This represents the first example of an organocatalytic electrocyclizahon reaction [62]. Notably, related asymmetric metal-catalyzed Nazarov cyclizations often provide the trans-product [63]. Later, Rueping applied N-triflyl phosphoramide 13e... 

The Nazarov Cyclization is a rare example of a Lewis acid-catalyzed 4-7t conrotatory electrocyclic reaction. Asymmetric... 

As with many asymmetric processes, there are three ways to control absolute stereochemistry in the Nazarov cyclization Asymmetry transfer, the use of chiral auxiliaries, or asymmetric catalysis. It is important to realize, however, that there are two distinct processes operating that determine the stereochemistry of the product. To control the absolute stereochemistry of the p-carbon atom(s), it is necessary to control the sense of conrotation, clockwise or counterclockwise (torquoselectivity, see Section 3.4.3). To control the absolute stereochemistry of the a-carbon atom however, it is necessary to control the facial selectivity for enol protonation. 

It is important to note that silyl-appended substrates have also demonstrated applicability in the control of torquoselectivity (see Section 3.4.3), and asymmetric transfer (see Section 3.4.4.4) in the Nazarov cyclization. 

An asymmetric Nazarov cydization of divinyl ketones bearing a-ester or a-amide groups has been reported [122]. The cyclizations of divinyl ketones (387) bearing a-ester groups proceed with moderate to good enantioselectivities in the presence... 

Another way to induce torquoselectivity involves the use of chiral catalysts. In 2003, Aggarwal and Belfield disclosed the first asymmetric Nazarov reaction catalyzed by a chiral LA complex (Scheme 3.16) [19]. It was found that a complex formed between copper bromide and tridentate ligand 71 was capable of controlling the conrotation of the cyclization of precursor 70 in good enantioselectivity and yield. With substrate attached, the resulting complex 73... 

Almost 10 years after Aggarwal s report, Rawal and coworkers [22] reported the use of chiral chromium-salen complexes to catalyze enantioselective Nazarov cyclizations. While other asymmetric Nazarov reactions had been reported since Aggarwal s publication, the chromium-salen complex 86 was the first to cat-alytically perform the cydization of unactivated divinyl ketones 84 to give cyclic ketones 85 in high diastereoselectivity and enantioselectivity (Scheme 3.19). 

Besides chiral phosphoric acids, also chiral imidodiphos-phoric acids 161 [72], disulfonimides 162 [73], or trifly-limides 163 [74] have emerged as powerful (Brpnsted or Lewis) acid organocatalysts for challenging asymmetric transformations like spiroacetalizations, Mukaiyama aldol reactions, or Nazarov cyclizations (Scheme 6.27). 

Optically active allenes have been extensively studied by Tius for the asymmetric formation of the corresponding Nazarov cyclization products (Scheme 16.36) [132, 133], As an illustrative example, cyclization of enone 264 furnished cyclopentenone 265 with a high degree of stereoinduction (95% ee) [132], The intermediate cyclization precursor 264 had been prepared by addition of vinyllithium 263 to optically active allene amide 262 (98% ee). 

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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