Cascade cyclizations

As an alternative to polyepoxide cyclization, cascade cyclization of cyclic sulfates... 

In another interesting application of this procedure, the acid-mediated cascade cyclization of (3-diketone diepoxide 73 involves the participation not only of the two oxirane rings and of the secondary alcoholic group, but also of one of the two carbonyl groups. In this way, besides the two adjacent C and D THF rings, the simultaneous construction of the spiroketal function between the B and C rings of etheromycin is obtained (compound 74, in a 70 30 mixture with 12 -epi compound Scheme 8.19) [37]. 

Harring, S. R. Livinghouse, T. Polyene cascade cyclizations mediated by BF3CH3N02. An unusual efficient method for the direct, stereospecific synthesis of polycyclic... 

The asymmetric cascade cyclization-hydrosilylation of triene 89 under similar conditions gave bicyclopentane derivative 90 in a high yield, although the enantioselectivity was diminished (Scheme 29).84b... 

Grigg expanded his Pd-catalyzed cascade cyclization reactions to include carbonylation as the termination step [427]. Thus, indoline 329 is obtained in excellent yield and the spiroindoline 330 is secured as a single diastereomer. Thallium acetate results in significant improvement in these reactions by allowing for low-pressure carbonylation. 

Et3B-induced radical cascade reactions with 1,5-enynes and 1,5-diynes have been applied to the synthesis of dioxatriquinanes and tricyclic glucocon-jugates (Scheme 17) [44,45]. Some of these elegant cascade cyclizations were also performed under mild conditions at - 50 °C. 

McDonald and coworkers studied a series of tandem endo-selective and stereospecific oxacyclization of polyepoxides by reaction with Lewis acid [92-95]. Polyepoxides, such as 50, can be obtained from the epoxidation of triene 49 with ketone 26 (Scheme 8). This cascade cyclization of polyepoxides provides an efficient method to synthesize substituted polycyclic ether structures, which are present in a number of biologically active marine natural products. 

Radical cyclization is an effective approach to the synthesis of isoquinolines (Scheme 8). In some cases these offer an alternative to the palladium-catalyzed reactions with aryl halide intermediates <99EJOC1925, 99TL1125>. For example, the radical cyclization of the iodide 37 onto the vinylsulfide moiety was followed by a cascade cyclization to form the benzo[n]quinolizidine system <99TL1149>. In some cases the radical cyclization can take place without the need for a halo intermediate. The reactive intermediate of 38 was formed on the nitrogen as an amidyl radical, which underwent tandem cyclizations to the lycorane system <99TL2125, 99SL441>. 

Cascade Cyclizations Involving C-H Bond Activation of an Arene 328... 

Tricyclic skeletons such as 85, 87, 89 with a central benzene ring are formed in the fully intramolecular Pd-catalyzed cascade cyclization of 2-bromo-l-ene-//,w-diynes 84, 86, 88 and analogs (Scheme 24). This process involves two alkyne relays in a row and a final 67r-electrocyclization or 6-endo-trig carbopalladation with ensuing / -dehydropalladation. 

With (i ,i )-BINAP as the ligand, Keay and Lau have been able to achieve the cascade cyclizations of the dienyl-substituted aryl triflates 134 toward the total synthesis of the natural product (+)-halenaquinone with ee s of up to 96% (Scheme 35). For these substrates, they observed an interesting influence of the remote substituent in 134. ... 

Narasaka efal. have extended these crochet-mode cascade cyclizations to di- and trienyl-substituted o-pentafluoro-benzoyloximes 136 and 140, to furnish spirofused cyclic imines 139 and 141, respectively (Scheme 36)/" The latter structure has been found in some bioactive natural products such as cephalotaxine. 

Scheme 37 Two cascade cyclizations involving inter- or intramolecular carbopalladations of allenes.

The 2-bromotetradeca-l,13-diene-7-yne 160 with its terminal phenyl group apparently also prefers to undergo a cascade cyclization via a neopentylpalladium intermediate with attack on the eventually proximal phenyl group to yield the pentacyclic system 161 (Scheme 39). ... 

Multiple Ring Forming Processes 11.11.7.1 Cascade Cyclization/Hydrosilylation of Trienes... 

Yttrocene complexes catalyze the cascade cyclization/hydrosilylation of trienes to form saturated silylated bicyclic compounds.For example, reaction of the 4-silyloxy-4-vinyl-l,6-hexadiene 69 and phenylsilane catalyzed by Gp 2YMe(THF) at room temperature for 1 h followed by oxidation of crude 70a gave [3.3.0]bicyclic diol 70b in 73% yield over two steps as a single diastereomer (Scheme 18). Selective conversion of 69 to 70a presumably requires initial 1,2-hydrometallation of one of the less-hindered G=G bonds to form alkylyttrium alkene complex II (Scheme 18). Selective S-exo carbometallation of II in preference to -exo carbometallation would form cyclopentyl-methylyttrium complex III (Scheme 18). Gyclization of III via a chairlike transition state would form the strained /r< /75 -fused alkylyttrium complex IIIl, which could undergo silylation to form 70a. 

Yttrium-catalyzed cascade cyclization/hydrosilylation was also applied to 3-substituted 4-vinyl-1,6-hexadienes. For example, reaction of 5y/7-3-(/ r/-butyldimethylsiloxy)-4-ethenyl-l,6-heptadiene syn-l ) with phenylsilane catalyzed by Gp 2YMe(THF) gave 72a in 72% yield as a 2.1 1 mixture of diastereomers (Equation (47)). Yttrium-catalyzed cascade reaction of the corresponding diastereomer anti-1 was more effective and gave 72b in 78% yield as a 7.2 1... 

Employment of the less sterically hindered yttrocene catalyst [(Cp )2YMe]2 or the more reactive zwitterionic zirconocene catalyst Cp 2ZrMe(/x-Me)B(C6E5)3 allowed cascade cyclization/hydrosilylation of trienes that possessed one or more 1,1-disubstituted alkene. As examples, reaction of 2-(3-butenyl)-l,6-hexadiene and phenylsilane catalyzed by [(Gp )2YMe]2 gave silylated spirocycle 74 in 88% yield. Likewise, the reaction of the dialkenyl alkylidene cyclopentane 75 gave silylated propellane 76 in good yield (Equations (50) and (51)). 

Yttrium-catalyzed cascade cyclization/hydrosilylation of 3-(3-butynyl)-l,5-hexadienes was stereospecific, and syn-19 (R =Gy, R = OGPh3) underwent cascade cyclization/hydrosilylation to form 80b (R = Gy, R = OGPh3) in 97% yield as a single diastereomer (Scheme 20). The regio- and stereoselective conversion of syn-19 to 80b was proposed to occur through an initial 5- x -intramolecular carbometallation via a chairlike transition state that resembles alkenyl olefin eomplex syn- m. followed by S-exo intramolecular carbometallation via a boatlike transition state that resembles alkyl olefin complex boat-llm. The second intramolecular carbometallation presumably occurs via a boatlike transition state to avoid the unfavorable 1,3-interaction present in the corresponding chairlike transition state (Scheme 20). 

Several additional points regarding the yttrium-catalyzed cascade cyclization/hydrosilylation of dienynes are worth noting. First, substitution at the 4-position of the 3-(3-butynyl)-l,5-hexadiene and a branched substituent on the terminal alkyne carbon atom were required to achieve high chemo- and regioselectivity. 

Rhodium carbonyl complexes catalyze the silane-initiated cascade cyclization of 1,6,11-triynes to form fused aromatic tricyclic compounds. For example, reaction of 83 [X = G(G02Et)2] with methyldiphenylsilane catalyzed by the tetrarhodium carbonyl cluster Rh4(GO)i2 in toluene at room temperature gave an 88 12 mixture of the silylated and unsilylated fused tricycles 84a and 84b [X = G(G02Et)2] in 85% combined yield (Equation (55)). The ratio of silylated to unsilylated tricyclic product formed in the reaction of 1,6,11-triynes was dependent on the nature of the substrate (Equation (55)). For example, Rh4(GO)i2-catalyzed reaction of diaminotriyne 83 (X = NBn) with methyldiphenylsilane gave unsilylated tricycle 84b (X = NBn) in 92% yield as the exclusive product (Equation (55)). 

Rhodium-catalyzed, silane-initiated cascade cyclization of 1,6,11-triynes 83 was proposed to occur via a silane-initiated cascade carbocyclization to form the silylated bicyclic triene (Z,Z)-In. / -Migratory insertion of the silylated G=G bond into the Rh-G bond of (Z,Z)-In followed by / -hydride elimination from frans-lln could then form 84a. Alternatively, cisitrans isomerization of (Z,Z)-In followed by / -migratory insertion of the silylated G=G bond into the Rh-G bond of resulting isomer ( ,Z)-In could form cis-Wn. Subsequent / -silyl elimination from m-IIn would form unsilylated tricycle 84b (Scheme 21). 

Rhodium carbonyl complexes also catalyze the cascade cyclization/hydrosilylation of 6-dodecene-l,l 1-diynes to form silylated tethered 2,2 -dimethylenebicyclopentanes. For example, reaction of ( )-85 with dimethylphenylsilane catalyzed by Rh(acac)(CO)2 in toluene at 50 °G under GO (1 atm) gave 86a in 55% yield as a single diastereomer (Equation (56)). Rhodium-catalyzed caseade cyclization/hydrosilylation of enediynes was stereospecific, and reaction of (Z)-85 under the conditions noted above gave 86b in 50% yield as a single diastereomer (Equation (57)). Rhodium(i)-catalyzed cascade cyclization/hydrosilylation of 6-dodecene-1,11-diynes was proposed to occur via silyl-metallation of one of the terminal G=G bonds of the enediyne with a silyl-Rh(iii) hydride complex, followed by two sequential intramolecular carbometallations and G-H reductive elimination. ... 

In contrast to the reactivity of 6-dodecene-1,11-diynes, rhodium-catalyzed reaction of l-dodecene-6,11-diynes with silane led not to cascade cyclization/hydrosilylation but rather to carbonylative tricyclization. For example, reaction of 87 [X = G(G02Me)2] and dimethylphenylsilane catalyzed by Rh(acac)(GO)2 in THE at room temperature under GO gave the cyclopenta[e]azulene 88 in 92% yield as the exclusive product (Scheme 22). Although the protocol was... 

The same type of cascade cyclization has been applied to the one-step synthesis of fused azabicyclic compounds with medium to large-membered rings (Scheme 10). ... 

Vitamin E is a collective term for all of the tocopherols and tocotrienols. Of these, one of the most active is (-)-o-tocopherol 6. Lutz Tietze of the Universitiit Gottingen has reported (Angew. Chem. bit. Ed. 2005,44,257) that the Pd-catalyzed cascade cyclization of 4 to 5 proceeds with 96% . 

We (J. Org. Chem. 2004,69, 7234) used the power of the Sharpless oxidations to convert the prochiral 10 into the epoxy diol 11. Base-catalyzed cascade cyclization then converted 11 into crystalline 12, again with high diastereomeric and enantiomeric purity. An advantage of this approach is that by changing the absolute sense of the epoxidation and/or the dihydroxylation, it should be possible to selectively prepare each of the four enantiomerically-pure diastereomers of 12. 

Intramolecular cascade cyclization of compounds 481 in the presence of catalytic amount of HgCl2 gave l,2,3,4-tetrahydro-6H-pyrido[l,2-a]pyr-azin-6-ones 483 (09TL4050). NMR investigations indicated that the reaction goes through intermediate 482, which then cyclized to 483. In the absence of catalyst, the cyclization was found to be sluggish. When instead of (2-N02-Ph)S02 derivative N-benzyloxycarbonyl derivative was used, no cyclized product was obtained. Similar reaction of compound 484 provided a mixture of tricyclic compounds 485 and 486. 

Palladiun-catalyzed two component cascade cyclization of 1-iodo-vinylbenzenes 489 and sulfonamide 490 gave 6-substituted 2-tosyl-ll-methylene-2,3,4,6,11,1 la-hexahydro-lH-pyrazino[l,2-b]isoquinolines 491 (07T6152). 

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