Cascade double addition-cyclization

Four cationic palladium intermediates in the Pd(0)-catalysed three-component cascade double addition-cyclization of organic halides, 2-(2,3-allenyl)malonates, and imines have been characterized by the high-resolution ESI-FTMS technology.84... 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

The second part of lanosterol biosynthesis is catalyzed by oxidosqualene lanosterol cyclase and occurs as shown in Figure 27.14. Squalene is folded by the enzyme into a conformation that aligns the various double bonds for undergoing a cascade of successive intramolecular electrophilic additions, followed by a series of hydride and methyl migrations. Except for the initial epoxide protonation/cyclization, the process is probably stepwise and appears to involve discrete carbocation intermediates that are stabilized by electrostatic interactions with electron-rich aromatic amino acids in the enzyme. 

Radical reaction cascades can be initiated by (TMS)3Si radical addition to unsaturated bonds. Two recent examples are illustrated in equations 54 and 55. The reaction of (TMS)3SiH with the 1,6-enyne derivative 98 afforded the 6-membered cyclic compound having exclusively the exocyclic double bond in E configuration via a 6-exo mode106. On the other hand, hydrosilylation of 99 afforded the 6-membered ring via a 6-endo cyclization of the vinyl radical onto the C=N bond107. 

Carretero and co-workers reported that the a-sulfonyl radicals resulting from such radical additions to y-oxygenated-a,P-unsaturated sulfones are useful intermediates for the generation of a second carbon-carbon bond via intramolecular addition to a suitably located carbon-carbon double bond.46,47 The highly functionalized acyclic y-hydroxy vinyl sulfone 68 underwent a novel cascade process, based on two sequential radical cyclizations, affording the bicyclic compounds 69 and 70 in good yield (Scheme 18). 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Grigg and co-workers [203] have very recently described an ingenious cascade process. Tliis is initiated by the addition of Bu3SnH to alkyne cyclization and anion capture follow and afford polycyclic products (Scheme 4-52). A palladium-catalyzed hydrogenation of the double bond in ajS-unsaturated A -acyloxy azolidinones was described by Wu et al. [204] the diastereoselectivity was low. 

Cooper et al. reported that the cascade reaction of the palladium-catalyzed cyclization and the Barbier-type allylation of the 1,3-diene-aryl iodide 514, the aldehydes 515, and indium gave the heterocycles 516 in good yields (Scheme 154).220b The reaction proceeds through oxidative addition of a C—I bond of 514 to Pd(0) and subsequent insertion of a double bond of 517 to give the jr-allylpalladium intermediate 518. Transmetalation of the jr-allylpalladium 518 with indium leads to the allylindium complex 519, and the following reaction with the aldehydes 515 gives 516. 

The -fragmentation can be used as one of the cascade steps in processes which do not start from the addition of a sulfur-centered radical. Rearrangements of sulfur compounds, catalyzed by tributylstannyl radical, which lead to 3-vinyldihydrothiophene or dihydrothiopyran derivatives, have been developed [70]. The mechanism is shown in Scheme 15 the cyclic y9-thioalkyl radical 9, produced in two steps, fragments, thus producing the thiyl radical 10, which cyclizes in a 5- or 6-endo fashion onto the stannylated double bond subsequent elimination leads to the final heterocyclic compound. 

In an investigation related to the total synthesis of (-i-)-3a-hydroxyreynosin, Cuerva and Oltra discovered that the products of a Ti(III)-mediated epoxide-opening/cycUzation cascade varied with the presence or absence of water. In dry THF they obtained the product originally desired, with an exocyclic A [3,14] double bond, but the addition of water resulted in the formation of the reductively cychzed product in Scheme 1.4. Apparently H is transferred from the titanium-water complex to the cyclized radical [35-37]. 

Strategic exploitation of the molecular shape of lactone 309 was next utilized to install the desired stereogenicity at all positions on tricychc compound 311, a key intermediate targeted as the substrate for a reductive cyclization cascade. The quaternary center at the lactone a-position was first addressed. Deprotonation with hthium diisopropylamide in THF and addition of 1-cyanobenzotriazole (BtCN) yielded an a-cyanolactone, which was then alkylated from the convex face of the molecule employing ethyl iodide in a mixture of warm acetonitrile and potassium carbonate to furnish lactone 310. The scaffold curvature was then exploited to epoxidize stereoselec-tively the double bond from the convex face to provide oxirane 311 following a Prilezhaev oxidation protocol. 

Intramolecular six-membered ring formation is also efficient. Treatment of bisdiene 62a with 0.05 equiv of a [Pd(OAc)2/3 PhjP] mixture in THF (65 °C, 24 h) affords the cyclized and intramolecularly trapped diene 63a in good chemical yield (82%) and with good diastereoselectivity (9 1 mixture of two diastereomers) (Scheme 20). The conversion of 62a to 63a is a unique cascade cyclization in that it constructs two new six-membered rings via the net 1,4-addition of the elements carbon and oxygen across a diene subunit. Three stereochemical elements are controlled in the cyclization of 62a to 63a. Two of these elements, the ( )-configuration of the double bond and the trans... 

Quinine-catalysed double Michael addition of CH2(CN)2 to dienones R CH=CHCOCH=CHR, followed by cyclization, afforded the corresponding cyclohexanones with 16 1 to >50 1 dr and <86% ee. This cascade represents an alternative route to enamine-iminium activation of enones. ... 

Additionally, dimedone derivative 360 and propargylamine 353 could be combined to give the alkynyl vinyl amine 361. The rearrangement cyclization cascade could be induced upon heating until reflux in chlorobenzene. The annulated piperidines 362 and 363 were isolated with 75 to 80% yield. In analogy to the cou-marin series, the product 362 displaying the exocyclic double bond was formed as the major product. The endocyclic olefin 363 was obtained as the side product (up to about 20%, Scheme 10.72). 

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