Enones Diels-Alder reaction

Because the Corey synthesis has been extensively used in prostaglandin research, improvements on the various steps in the procedure have been made. These variations include improved procedures for the preparation of norbomenone (24), alternative methods for the resolution of acid (26), stereoselective preparations of (26), improved procedures for the deiodination of iodolactone (27), alternative methods for the synthesis of Corey aldehyde (29) or its equivalent, and improved procedures for the stereoselective reduction of enone (30) (108—168). For example, a catalytic enantioselective Diels-Alder reaction has been used in a highly efficient synthesis of key intermediate (24) in 92% ee (169). 

Trifluoromethyl-l,3-dioxin-4-ones can act as the enone component in [2 + 2] or as dienophiles in Diels-Alder reactions and are potential synthons for enantiomerically pure trifluoromethyl aliphatics [92JCS-(Pl)1393). 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

Radical Diels-Alder reactions have been used mainly to synthesize polycyclic molecules. These reactions, like those that involve cations and anions as components, proceed quickly but generally do not give high yields. Thus, the tricyclic enone 14 is the result of an intramolecular Diels-Alder reaction of quenched vinyl radical intermediate 13 obtained by treating the iododienynone 12 with n-tributyltin hydride/2,2 -azobisisobutyronitrile (AIBN) [28] (Equation 1.11). 

The intramolecular Diels-Alder reactions of photochemically generated trans-cycloalk-enones [162]... 

An endo-selective ionic Diels-Alder reaction of a,/f-enone and a,/f-enal acetals catalyzed by electrogenerated acid [99]... 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

For a review of Diels-Alder reactions with cyclic enones, see Fringuelli, E Taticchi, A. Wenkert, E. Org. Prep. Proved. Int., 1990, 22, 131. 

Simple Example Lewis acids, such as AlCl, catalyse the Diels-Alder reaction. Workers used a three-fold excess of butadiene to react with the AlCl complex of 5,6 and 7-membered cyclic enones, e.g, (5), giving excellent yields of eie fused bicyclic ketones (6), Me and H must be cis in (6) as they were aiv in (5). 

The cyclohexene (ring C) can be disconnected by a Diels-Alder reaction to reveal enone (32) and diene (33). Pour chiral centres remain in (32) so three are Introduced in the Diels-Alder reaction. 

Cycloaddition of 2-cyanoalk-2-enones with several conjugated dienes proceeded under zinc chloride catalysis.636 Zinc halides have also shown reactivity with phenylacetylenes.637 Zinc chloride is an effective Lewis acid catalyst in the Diels Alder reactions of the keto esters and the effects on stereochemistry of catalysts used have been examined.638... 

Oxidative-pericydic processes, and in particular the oxidative/Diels-Alder reaction, are quite common in nature. The so-called Diels-Alderase is usually an oxidizing enzyme, which induces, for example, the formation of a suitable dienophile such as an enone from an allylic alcohol [49]. 

Although Lewis acid-catalyzed-Diels-Alder reactions of enones are common, there are few reports on the catalysis of Diels-Alder reaction of nitroalkenes. The reaction of nitroalkenes with alkenes in the presence of Lewis acids undergoes a different course of reaction to give cyclic nitronates (see Section 8.3). Knochel reported an enhanced reactivity and selectivity of the intramolecular Diels-Alder reaction using silica gel as Lewis acid in hexane (Eq. 8.19).31... 

Interestingly, we were intrigued by the ESI mass spectrum of the compound, as the observed base peak consisted of [M-S02+Na]+. This led us to explore a thermal retro-Diels-Alder reaction that could afford the desired enone 69. It is noteworthy that the chemistry of cyclic enol-sulfites would appear to be an under-explored area with a few references reporting their isolation being found [57]. At last, we were also able to prepare epoxy ketone 70 from 69 in three steps, albeit epoxidation did not take place unless the TES group was removed. Spartan models reaffirmed our initial conformational assessment of enone 69 and epoxy ketone 70, which contain sp3-hybridized C8a and s/r-hybridized C8b (p s e u d o-. v/r - h y b r i d i zed C8b for 70) at the AB-ring junction (Fig. 8.12) and displayed the desired twisted-boat conformation in A-ring. 

Microwave heating has also been employed for performing retro-Diels-Alder cycloaddition reactions, as exemplified in Scheme 6.94. In the context of preparing optically pure cross-conjugated cydopentadienones as precursors to arachidonic acid derivatives, Evans, Eddolls, and coworkers performed microwave-mediated Lewis acid-catalyzed retro-Diels-Alder reactions of suitable exo-cyclic enone building blocks [193, 194], The microwave-mediated transformations were performed in dichloromethane at 60-100 °C with 0.5 equivalents of methylaluminum dichloride as catalyst and 5 equivalents of maleic anhydride as cyclopentadiene trap. In most cases, the reaction was stopped after 30 min since continued irradiation eroded the product yields. The use of short bursts of microwave irradiation minimized doublebond isomerization. 

This chapter deals with [2 + 2]cycloadditions of various chromophors to an olefinic double bond with formation of a four-membered ring, with reactions proceeding as well in an intermolecular as in an intramolecular pattern. Due to the variety of the starting materials available (ketones, enones, olefins, imines, thioketones, etc.. . .), due to the diversity of products obtained, and last but not least, due to the fact that cyclobutanes and oxetanes are not accessible by such a simple one-step transformation in a non-photo-chemical reaction, the [2+2]photocycloaddition has become equivalent to the (thermal) Diels-Alder reaction in importance as for ring construction in organic synthesis. 

The high enantioselectivity shown in the above reactions can be attributed to two important factors. First, coordination of the Lewis acid with the a-hydroxy ketone moiety of dienophile 17 or 19 leads to the formation of a rigid five-membered chelate 21. This chelate causes the differentiation of the two dia-stereotopic faces of the enone system. Second, arising from the established absolute configuration of 17 and 19, within 21, the Diels-Alder reaction proceeds with the enone fragment at its cisoid position (yyu-planar). 

In the highly competitive arena surrounding the Pfizer compounds CP-263,114 and CP-225,917 (Figure 4.2), Nicolaou and co-workers employed a hydrozirconation—iodination sequence to produce vinyl iodide 4 [17]. Lithium—halogen exchange and subsequent conversion to enone 5 sets the stage for a Lewis acid assisted intramolecular Diels—Alder reaction affording polycyclic 6 as the major diastereomer (Scheme 4.3). 

In total, over the past six years, the chelating P,N-ligands have shown considerable promise in a variety of enantioselective processes, including transfer-hydrogenation and hydrosilylation of ketones, hydroboration of alkenes, conjugate addition to enones and Lewis-acid catalysed Diels-Alder reactions, in addition to those described above.128,341 It is anticipated that this list will continue to grow, and... 

Cycloadditions and cyclization reactions are among the most important synthetic applications of donor-substituted allenes, since they result in the formation of a variety of carbocyclic and heterocyclic compounds. Early investigations of Diels-Alder reactions with alkoxyallenes demonstrated that harsh reaction conditions, e.g. high pressure, high temperature or Lewis acid promotion, are often required to afford the corresponding heterocycles in only poor to moderate yield [12b, 92-94]. Although a,/3-unsaturated carbonyl compounds have not been used extensively as heterodienes, considerable success has been achieved with activated enone 146 (Eq. 8.27) or with the electron-deficient tosylimine 148 (Eq. 8.28). Both dienes reacted under... 

Baldwin and coworkers82 studied the Diels-Alder reactions between dihydropyri-dinium ions and diene 77 with the aim to synthesize functionalized hydroisoquinolines. The reaction of diene 77 with dihydropyridinium ion 79, which was prepared in situ by treating 78 with zinc bromide, afforded 80. After acidic work-up, a mixture of methoxyke-tone 81 and enone 82 was obtained (equation 25). The reaction proceeded with complete exo selectivity. Without the addition of zinc bromide, no Diels-Alder reaction was observed. 

The key chiral intermediate 4, highly functionalized hydroisoquinoline, was obtained by a Diels-Alder reaction between siloxydiene 5 and chiral dienophile 6 which was prepared from Z-serine [4]. Ruche reduction of enone 4 gave allyl alco-... 

Both enantiomers of the bicyclic enone 78 and their derivatives have been proved to be useful chiral building blocks for the synthesis of natural products [29], among them y-butyrolactones. 78 is readily available in either enantiomeric form by a Diels-Alder reaction of furan with a-acetoxyacry-lonitrile and subsequent hydrolysis, followed by a resolution of the racemate... 

Reactions where NLE have been discovered include Sharpless asymmetric epoxi-dation of allylic alcohols, enantioselective oxidation of sulfides to sulfoxides, Diels-Alder and hetero-Diels-Alder reactions, carbonyl-ene reactions, addition of MesSiCN or organometallics on aldehydes, conjugated additions of organometal-lics on enones, enantioselective hydrogenations, copolymerization, and the Henry reaction. Because of the diversity of the reactions, it is more convenient to classify the examples according to the types of catalyst involved. 

Diels-Alder, imino dienophiles, 65, 2 Diels-Alder, intramolecular, 32, 1 Diels-Alder, maleic anhydride, 4, 1 [4 -h 3], 51, 3 of enones, 44, 2 of ketenes, 45, 2 of nitrones and alkenes, 36, 1 Pauson-Khand, 40, 1 photochemical, 44, 2 retro-Diels-Alder reaction, 52, 1 53, 2 [6-h4], 49, 2 [3-h2], 61, 1 Cyclobutanes, synthesis ... 

Danishefsky dienes [98] cycloadd to Cjq in refluxing toluene or benzene [5, 38, 99-101]. The diene 103 adds in 60% yield to Cjq to give the desilylated ketone 104 [5,101]. Acid-catalyzed methanol elimination then furnishes the enone 105 in 82% yield (Scheme 4.17). As already described, this enone can be reduced by DIBAL-H to the corresponding alcohol for further functionalization. The same a,(3-un-saturated alcohol can also be obtained in better yield by Diels-Alder reaction of Cg0 with butadiene, followed by oxidation with singlet oxygen to the allylic hydroperoxide and PPhj reduction to the desired alcohol [101]. This sequence yields the allylic alcohol in 53%, starting from Cjq without the need of isolating intermediates. 

The enedione (15), a tetracyclic intermediate on a synthetic route to fusidic acid, has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3). This compound (24) has also been prepared by degradation of fusidic acid. Attempts to introduce the C-11 oxygen function necessary for the synthesis of fusidic acid have not been very... 

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