Electrocyclic reactions Nazarov cyclization

Upon treatment of a divinyl ketone 1 with a protic acid or a Lewis acid, an electrocyclic ring closure can take place to yield a cyclopentenone 3. This reaction is called the Nazarov cyclization Protonation at the carbonyl oxygen of the divinyl ketone 1 leads to formation of a hydroxypentadienyl cation 2, which can undergo a thermally allowed, conrotatory electrocyclic ring closure reaction to give a cyclopentenyl cation 4. Through subsequent loss of a proton a mixture of isomeric cyclopentenones 5 and 6 is obtained ... 

The Nazarov cyclization of vinyl aryl ketones involves a disruption of the aromaticity, and therefore, the activation barrier is significantly higher than that of the divinyl ketones. Not surprisingly, the Lewis acid-catalyzed protocols [30] resulted only in decomposition to the enone derived from 46,47, and CO. Pleasingly, however, photolysis [31] readily delivered the desired annulation product 48 in 60 % yield. The photo-Nazarov cyclization reaction of aryl vinyl ketones was first reported by Smith and Agosta. Subsequent mechanistic studies by Leitich and Schaffner revealed the reaction mechanism to be a thermal electrocyclization induced by photolytic enone isomerization. The mildness of these reaction conditions and the selective activation of the enone functional group were key to the success of this reaction. 

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

Nazarov cyclizations require acid, and protonation of the ketone sets up the conjugated k system required for an electrocyclic reaction. 

The most recent and powerful example of supramolecular catalysis comes from an elegant combination of the principles delineated above. The Nazarov cyclization can be used to prepare Cp (pentamethylcyclopentadiene) from a mixture of pentanedienols, as in Fig. 20. This reaction requires formation of a carbocation by dehydration of the protonated alcohol, and then electrocyclization of the corresponding bis-allylic carbocation. 

A third and critical advance in the development of the Nazarov cyclization was the demtmstration that it belongs to the general class of cationic electrocyclic reactions (Scheme 4). This broadened its definition to include reactions which involve pentadienylic cations or equivalents and thus expanded the range of precursors for cyclopentenones. Further, the stereochemical features of electrocyclization enhanced the utility of the reaction and, in addition, stimulated the development of a photochemical variant. 

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 Nazarov cyclization is an example of a 47r-electrocyclic closure of a pentadienylic cation. The evidence in support of this idea is primarily stereochemical. The basic tenets of the theory of electrocyclic reactions make very clear predictions about the relative configuration of the substituents on the newly formed bond of the five-membered ring. Because the formation of a cyclopentenone often destroys one of the newly created centers, special substrates must be constructed to aUow this relationship to be preserved. Prior to the enunciation of the theory of conservation of orbital symmetry, Deno and Sorensen had observed the facile thermal cyclization of pentadienylic cations and subsequent rearrangements of the resulting cyclopentenyl cations. Unfortunately, these secondary rearrangements thwarted early attempts to verify the stereochemical predictions of orbital symmetry control. Subsequent studies with Ae pentamethyl derivative were successful. - The most convincing evidence for a pericyclic mechanism came from Woodward, Lehr and Kurland, who documented the complementary rotatory pathways for the thermal (conrotatory) and photochemical (disrotatoiy) cyclizations, precisely as predicted by the conservation of orbital symmetry (Scheme 5). 

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. 

Nazarov cyclization reaction. Synthesis of cyclopentenones by the acid-catalyzed electrocyclic ring closure of divinyl or allylvinyl ketones available by hydration of divinylacetylenes. 

Electrocyclic reactions are not limited to neutral polyenes. The cyclization of a pentadienyl cation to a cyclopentenyl cation offers a useful entry to five-membered carbocycUc compounds. One such reaction is the Nazarov cyclization of divinyl ketones. Protonation or Lewis acid complexation of the oxygen atom of the carbonyl group of a divinyl ketone generates a pentadienyl cation. This cation undergoes electrocyclization to give an allyl cation within a cyclopentane ring. The allyl cation can lose a proton or be trapped, for example by a nucleophile. Proton loss occurs to give the thermodynamically more stable alkene and subsequent keto-enol tautomerism leads to the typical Nazarov product, a cyclopentenone (3.220). 

One noteworthy example of an electrocyclic ring-closing reaction is the Nazarov cyclization, which converts divinyl ketones into cyclopentenes, usually in the presence of an acid. 

They are examples of what is known, after its Russian discoverer, as the Nazarov cyclization. In its simplest form, the Nazarov cyclization is the ring closure of a doubly a, 3-unsaturated ketone to give a cyclopentenone. Nazarov cyclizations require acid, and protonation of the ketone sets up the conjugated n system required for an electrocyclic reaction. 

The Nazarov cyclization reaction may be defined as an acid (protic or Lewis) induced cationic Trr-electrons electrocyclic ring closure reaction of a,a -divinyl ketones to form cyclopentenones. 

Silicon-directed Nazarov cyclization Activation of the ketone 1 by a Lewis acid catalyst generates a pentadienyl cation, which undergoes a thermally allowed 4Tr-electron conrotatory electrocyclization (Scheme 2.19). This generates a silicon-stabilized cation, which undergoes an elimination reaction of silyl group to give the cyclopentadienol. Subsequent tautomerization of cyclopentadienol produces the cyclopentenone product 2. 

Nazarov-type Reactions. It has been shown that the highly Lewis acidic Sc(OTf)3 and Yb(OTf)3 can catalyze the Nazarov cyclization. Recently, Dy(OTf)3 has been err5>loyed to catalyze the rearrangement of furfural and furylcarbinol reagents. These rearrangements are proposed to terminate in Nazarov-type 47T electrocyclizations. A Dy(OTf)3-catalyzed formation of trans-4,5-diamino-2-cyclopenten- 1-ones fromfurfural and nitrogen nucleophiles has been disclosed (eq 5). ... 

Electrocyclization reactions are powerful synthetic tools to prepare compounds of great molecular diversity. These reactions allow for the formation of many substituted cyclic and polycychc compounds important in medicine, materials science, cosmetics, and so on. The well-established mechanisms and predictable outcomes of electrocyclization reactions permit the elaboration of logical blueprints for the synthesis of important molecules. Among these, the Nazarov cyclization is a salient member of the family. Reported first in 1941 by Ivan Nikolaevich Nazarov [1], this reaction has been studied extensively and many variations and applications have been developed over the years. In this chapter, we will present selected examples highlighting the versatility and synthetic power of this transformation [2]. In its simplest form, the Nazarov employs a divinyl ketone as the starting material, a cross-conjugated compound which can be regarded as a 3 -oxa-[3]dendralene. 

A detailed investigation was later reported by Frontier in which a conrotatory electrocyclization of silyloxyfurans 79 was catalyzed by the same Ir(III) complex (76) to produce lactones 80 in good yield. This work culminated in the total synthesis of racemic merrilactone A (83) (Scheme 3.18) [21]. Generally, only one diastereoisomer was isolated from the Nazarov reaction. These cyclizations also demonstrated complete transfer of the trialkylsilyl group from the silyloxyfuran to the ketone oxygen. It had been previously demonstrated that trialkylsilyl species can catalyze the Nazarov reaction further experiments showed that although... 

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. 

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). 

The Nazarov reaction [196] is a conrotatory electrocyclization involving four electrons over a five-carbon span. Usually, a more highly substituted cyclopentenone is obtained. However, contrathermodynamic products may be generated by placing a silyl group at the p-position of a bare vinyl moiety in the cross-conjugated dienone [197]. The acceptor facilitates and controls the regiochemistry of the cyclization process. 

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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