Annulation Nazarov cyclization

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. 

In reactions between Wtosylpyrrole and crotonic or cinnamic acid in the presence of TFAA only 2-acylation products 390 were isolated, along with traces of the Michael adduct 391 in the case of later acid no Nazarov cyclization with crotonic and cinnamic acid was observed (Equation 91) <20060L163>. With 3,3-dimethylacrylic acid direct 2-acylation and annulation of Wtosylpyrrole occurs to give compounds 392 and 393, respectively (Equation 92). 

A usefid feature of the Nazarov cyclization is the construction of fused bicyclic systems by annulation of a flve-membered ring. This requires one of the vinyl groups to be embedded in a ring. These precursors can be formed easily by vinyl alkyne addition to cyclic ketones followed by dehydration and hydrolysis. This procedure woiks well for symmetrical ketones but it gives regioisomers from unsymmetrical ketones such as 1- or 2-octalone."- A superior method, reported by Paquette, 76 involves the acylation of cycloalkenylsilanes to provide divinyl ketones (equation 6). The advantages of this protocol are discussed in Section 6.3.7.4.3. 

A significant advance in the use of Friedel-Crafts acylation of alkenes to prepare divinyl ketones was the employment of vinylsilanes to control the site of electrophilic substitution. Two groups have developed this approach to cyclopentenone annulation using slightly different strategies. In the method described by Magnus the reagent vinyltrimethylsilane (80) is used primarily as an ethylene equivalent (equation 44). The construction of bicyclic systems followed readily as Nazarov cyclization proceeded under the reaction conditions. Tin(lV) chloride was found to be the most effective promoter of the overall transformation. As expected the position of the double bond is thermodynamically controlled. 

Another synthetically useful carbon bond-forming reaction involves reaction of diiron nonacarbonyl with halo-carbonyl compounds. Noyori found that a,a -dibromoketones (498) react with diiron nonacarbonyl [Fe2(CO)9] to give an iron stabilized alkoxy zwitterion (499). The intermediate Jt-allyl iron species reacts with alkenes in a stepwise manner (initially producing 500) to give cyclic ketones such as 501, 23 and the product is equivalent to the product of a [3-t2]-cycloaddition with an alkene (sec. 11.11). This cyclization method is now known as Noyori annulation. This reaction is related to the Nazarov cyclization previously discussed in Section 12.3.C. Enamines can react with 498, but the initially formed enamino ketone product eliminates the amino group to form cyclopentanone derivatives. Intermediates such as 499 may actually exist as cations hound to a metal rather than as the alkoxide-iron structures shown.323b-d noted that Zn/B(OEt)3 is... 

One particularly elegant use of the silicon-directed Nazarov cyclization was in the synthesis of the angular triquinane silphinene (89), by Miesch and co-workers. Addition of a large excess of boron trifluoride etherate in refluxing ethylbenzene to 86 ensured annulation of the required third ring. Notably, the benzyloxy group was also eliminated imder the reaction conditions, and the product 88 was subsequently converted into the natural product 89. 

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). 

The carbonylative coupling reaction followed by a Nazarov cyclization is utilized for a sequential annulation to assemble the fused five-membered ring structure of marine natural product A -capnellene (Scheme 22). ... 

A full report has been published on the annulation of the -keto-ester (83) by the cyclopropylphosphonium salt (84) leading to (85) hydrolysis of the intermediate vinyl sulphide was effected by an iodolactonization procedure, as standard methods failed. An alternative annulation method (Scheme 8) involves the acylation of vinyl cuprates by unsaturated acid chlorides followed by Nazarov cyclization MeaSil can sometimes serve as a good reagent for this step. Nazarov-type cyclizations using acetylenic acetals have also been employed in... 

The promise suggested for the recently described (Vol. 4, p. 252) method of cyclopentenone annulation, based on vinyl silane directed Friedel-Crafts acylation followed by Nazarov cyclization (Scheme 7) has been fully vindicated with... 

Mehta has examined relative stereocontrol in an approach to the carbocyclic nucleus of ophiobolins. Cyclization of the triquinane (11) gave two products, (12) and (13), in a 4 1 ratio (Scheme 14). These products arise from opposite rotatory pathways as shown. Surprisingly, the major product arises from conrotation to the concave face of the diquinane unit. Finally, Nazarov has provided an interesting example of both fused and spiro mode annulations in equation (10). ... 

The synthesis of a cyclopentadienyl-annulated imidazolium salt 282 was accomplished through a Nazarov-type cyclization as a key transformation. This annulation step was affected by toluenesulfonic acid via protonation-dehydration of the tertiary allylic alcohol 278 to form a three-centered carbocation, which was then annulated, in an electrophilic fashion, onto the C-4 position of the imidazole to form 279. The formation of the alcohol 278 was achieved via lithiation of imidazole 276 and then quenching with ketone 277 to give the 1,2-addition product (Scheme 70) <2005TL6847>. 

Solid-phase techniques are also used for synthesis of compounds with trans-decalin motif where the Robinson annulation is used for synthesis of some natural product inspired structures such as that of 75. The protocol uses an immobilized solid phase bound Nazarov reagent that reacts with the enamine of the starting ketone under basic conditions. After cyclization the product is released from the solid phase by using TBAF at room temperature overnight. For the products 75a-c only one stereoisomer was formed (de > 98%) with modest 22-38% yields. 

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