Enantioselectivity Nazarov cyclization

Scheme 3.16 Enantioselective Nazarov cyclization catalyzed by chiral copper complex.

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). 

Walz I, Togni A. Ni(II)-catalyzed enantioselective Nazarov cyclizations. Chem. Commun. 2008 4315-4317. 

Recently, Rueping et al. [36] disclosed the first enantioselective Nazarov cyclization reaction organocatalyzed by a chiral Brpnsted acid. The proposed reaction pathway involves a conrotatory 4n electrocyclization of the divinyl ketone 83 leading to the formation of an enol intermediate which is then snbjected to enantioselective protonation by the chiral Brpnsted acid 82b. This electrocyclization-protonation reaction was conducted with various divinyl ketones 83 under optimized conditions, i.e. in the presence of the chiral A -triflyl phosphoramide 82b (5 mol%) in chloroform at -10°C, affording the corresponding cyclopentenones 84 with 67-78% ee (for examples, see 83a-c 84a-c, Scheme 3.44). 

More recently, several approaches to catalytic, enantioselective Nazarov cyclizations have been developed [28]. Trauner reported that substrate 266 underwent electrocyclic rearrangement, furnishing 268 in 94 % ee in the presence of the chiral Sc-PYBOX catalyst 267 (Equation 30) [134]. The enantio-discriminating step in this cyclization is believed to be protonation of the intermediate enolate that ensues from the Nazarov cyclization. Rueping has documented enantioselective cyclizations of related dienones in the presence of the chiral phosphoric acid derivative 270 (Equation 31) [135]. Chiral Bronsted acid catalysis thus effected the cyclization of 269 to give products 271 (87% ee) and 272 (95% ee). 

Table 11 Scope of the first enantioselective Brpnsted acid catalyzed Nazarov cyclization...

Rueping and co-workers have reported one of the most impressive examples of a Nazarov cyclization under asynunetric catalysis. They have shown that chiral Bronsted-acid catalysis outperforms the chiral Lewis acid catalysts used to date and have demonstrated the efficient cyclization of a variety of substrates 79 with moderate to excellent diastereoselectivity and good to excellent enantioselectivity. Only low catalyst loadings (2 mol %) are required of chiral acid 81 to catalyze the reaction efficiently. Interestingly, the reaction primarily generates the cw-cyclopentanones 80a, as opposed to the Lewis acid-catalyzed reactions that provide the trans-product (see 73). 

Quite recently. Rueping et al reported Nazarov cyclization reaction catalyzed by a phosphoramide (Scheme 2.107) [185]. Although phosphoric acid (41k) is effective for the Nazarov reaction, use of an N-triflyl phosphoramide (50b) improved the enantioselectivity. This is the first example of the enantioselective organocatalytic electrocyclization reaction. 

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. 

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

An interesting catalytic diastereo- and enantioselective tandem transformation via Nazarov cyclization /electrophilic fluorination has been efficiently promoted by a (/ ,/ )-Ph-BOX-Cu(II) complex to afford fluorine-containing 1-indanone derivatives with two new stereocenters with high diastereoselectivity trans/cis up to 49/1) and moderate-to-high enantioselectivities (up to 95.5% ee) (Scheme 44.24). This catalytic enantioselective tandem transformation can be used for synthesis of organofluorine compounds with adjacent carbon- and fluorine-substituted tertiary and quaternary stereocenters. " ... 

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... 

The Nazarov reaction belongs to a type of 4n electrocyclization and can usually be promoted by metal-based catalysts. In 2007, the first enantioselective organo-catalytic Nazarov reaction was reported by Rueping and coworkers [35aj. A chiral N-triflyl-phosphoramide 101 was a better selection for the cyclization of dienone substrates 102, and cyclopentenone products 103 were generated as a diastereo-meric mixture but with excellent enantioselectivity at low catalyst loadings (2 mol%) (Scheme 36.27). 

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