Substrates Nazarov cyclization

The majority of yc/n-dichIorocycIopropane substrates examined in this study provided the desired a-chlorocyclopentenones as a result of sequential electrocyclic ring opening and Nazarov cyclization. In general, those substrates lacking additional substitution on the cyclopropane moiety provided products 75 selectively as a result of regioselective elimination to deliver the more electron-rich olefin. The mechanism for this transformation is believed to involve disrotatory halocyclopropane ring opening... 

To further expand the scope of this new silver(I)-mediated reaction sequence, interrupted Nazarov cyclizations were explored using the halocyclopropane chemistry, an investigation that was prompted by the discovery of an intriguing result. It was found that treatment of the phenethyl-substituted compound 76 with 1.5 equiv of silver tetrafluoroborate in dichloromethane provided benzohydrindenone 77 as the sole product, with no apparent formation of the simple a-chlorocyclopentenone (Scheme 4.24). This prompted an examination of appropriately substituted gem-dichlorocyclopropane substrates in analogous interrupted Nazarov processes to ascertain the scope of this new cascade reaction sequence. 

Conditions have been optimized for the scandium triflate catalyzed Nazarov cyclization of thiophene substrates in the presence of LiClOa <20060L5661>. 

This coupling when carried out in the presence of carbon monoxide (15-50 psi) results in cross-coupled ketones in generally good yield." This reaction is a particularly attractive route to divinyl ketones, which are substrates for Nazarov cyclization. The geometry of the vinyl triflate is retained. 

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 facile elimination of -heterosubstituents in ketones allows for the ready construction of a,p-enones. Three different heteroatoms have been employed, chlorine, nitrogen and oxygen. The -chloro enones (products of Friedel-Crafts acylation) suffer Nazarov cyclization under standard conditions. -" Jacquier has prepared a series of -amino enones (31) from Mannich condensations." These substrates undergo cyclization in modest yields under standard conditions (equation 23). Takeda has found that the readily available" tetrahydro-4-pyranones (32) produce 2-cyclopentenone-4-carboxylates upon treatment with TMS-I (equation 24). " It is noteworthy that the putative a-carboalkoxy divinyl ketones have been independently cyclized by Marino using TMS-I. ... 

MeaSil and la can be used as Lewis acids in the Nazarov cyclization (Sch. 29) [57]. The success of the reaction depends on the substrates and on the reaction conditions. 

The short synthesis of (+)-frans-sabinene hydrate, an important flavor chemical found in a variety of essential oils from mint and herbs, was developed by C.C. Galopin. The key intermediate of the synthetic sequence was 3-isopropyl-2-cyclopentenone. Initially a Nazarov cyclization of a dienone substrate was attempted for the synthesis of this compound, but the cyclization did not take place under a variety of conditions. For this reason, a sequential Stetter reactionlintramolecular aldol condensation approach was successfully implemented. 

In the elaboration of cyclopentenones the Nazarov cyclization (not a cycloaddition reaction) also offers some advantages. Metal complexes including a V(IV) chelate of salen 60 and the Cu complex of ent-96B have been employed as catalysts. By structural demand of the substrate to induce rearrangement following the cyclization a synthesis of spirocycles is realized. 

The most widely used electron-donating a-substituents are alkoxy groups. Indeed, these substrates are so reactive that they enabled the first truly catalytic examples of Lewis acid-catalyzed Nazarov reactions. Whereas stoichiometric quantities of Lewis acid are often required due to slow protonation of the Lewis acid enolate, a-alkoxy appended systems show efficient catalytic turnover. For example, Trauner and co-workers reported the efficient Nazarov cyclization of 37 in the presence of 10 mol % of aluminium trichloride. " Not only do a-alkoxy groups lower the activation barrier to cyclization, but they also localize the resultant positive charge at one a-carbon, ensuring a highly regioselective elimination. 

Flynn and co-workers reported an efficient Nazarov cyclization of P-ketoesters, such as 44. Under Bronsted acid promotion, a range of substrates gave the tran -cyclopentanones after highly regioselective elimination, such as 45. Although they used predominately Z-configured substrates, it is important to note that E/Z isomerization occurs gradually over... 

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-... 

As opposed to these P-sp -hybridized systems, allenyl and cumulenyl substrates (P-sp-hybridized) exhibit excellent reactivity in the Nazarov cyclization. This enhanced reactivity is thought to derive from two factors Minimization of steric interactions at the P-position (increasing the... 

Examples do exist however, of productive Nazarov cyclizations bearing electron-rich heteroatoms in the P-position. For example, cyclization of substrate 60 (albeit with the nitrogen atom contained within an aromatic indole moiety) was reported by Cheng and co-workers in 1996. Exposure of 60 to HCl in refluxing dioxane resulted in the formation of product 61 in moderate yield. This key intermediate was then transformed into inverto-yuehchukene (62), a dimer of 2-didehydroprenylindole. 

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). 

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. 

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. 

An imaginative approach to the cephalotaxine alkaloids was reported by Li and co-workers and used a functional equivalent of the Nazarov cyclization. Iron-mediated oxidation of substrate 120 gave intermediate 121. Tautomerization of 121 to 122 followed by electrocyclization gave annulated product 123. This key intermediate was subsequently converted into cephalotaxine (124). 

In 2004, Frontier et al. found that iridium complex (154) is very reactive as a Lewis acidic promoter of Nazarov cyclization, especially relative to Cu(OTf)2 [48]. Recently, they have found that Ir (III) catalyst (154) is a strong Lewis acid capable of catalyzing Nazarov cyclization with great efficiency for various divinyl ketones (Scheme 16.41) [49]. The efficiency of the cyclization is attributed to the electrophilicity of the Ir(III) complex and substrate activation via 0,0 -chelation that employs two substrate carbonyl groups or one carbonyl and an ether function, and encourages the s-trans/s-trans conformation required for cyclization. 

When the coupling reactions of vinyl and aryl triflates are carried out in the presence of carbon monoxide and LiCl, good yields of the cross-coupled ketones are obtained (eqs 3 and 4). This is a particularly attractive route to divinyl ketones which are important substrates in the Nazarov cyclization. 

The initial product of the Nazarov cyclization is an allylic cation for which several reaction pathways may be available. It is often useful to be able to introduce a bias into the substrate that predisposes the cation to follow a single pathway that terminates the process. Denmark and... 

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). 

An early variant of the Nazarov cyclization119 employed an alkoxycarbonyl substituent and Lewis acid catalysis to facilitate the reaction. The cyclizations were described as temperamental", but did demonstrate the capability to facilitate the cyclization and control the site of the alkene in the cyclized product. For example, cyclization of the a,a -dienone 7 is promoted by the action of trimethylsilyl iodide to afford the /i-keto ester 8 in 48% yield. No studies in stereoinduction have been reported, but, given the recent advances in the design of chiral Lewis acids and the efficient chiral auxiliaries for the reactions of carboxylic acid esters, these substrates are potentially suitable candidates for such studies. 

Synthetic applications of the Nazarov reaction require substrates other than an unsubstituted l,4-pentadien-3-one. Indeed, substituents on the divinyl ketone moiety have a significant impact on reactivity. Steric and electronic effects of substituents play a major role regarding both substrate reactivity and the torquoselectivity (see Section 3.3.3) of the cyclization. 

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