Polycyclic Cascades

Polyethers are readily accessible by tandem radical cyclizations. For example, bis-allylether 480a,b reacts with a trimethyl tin radical and then undergoes a sequential radical cyclization to provide 481a,b in 86 and 85% yield, respectively (equation (13)) (92JA3115). A ceric ammonium nitrate oxidation of 481 was carried out in methanol and converted the stannyl moiety into the corresponding dimethylacetal. 

Several groups have reported the use of a radical cyclization cascade to form nitrogenous polycyclic structures. In one example, Parsons treated enamide 482 with 

Thioamides and thioureas also undergo the silyl-mediated cascade reaction. For example, compound 503 gave 504 in 67% yield, while structural variants generally afforded related cyclized products in 50-87% yield. Thiourea 505 provided 506 in 64% yield, although a related substrate whose alkyne tether was conformationally more flexible failed to produce any cyclized product. 

The difficulty associated with cyclization of the aminyl radical onto a Ji-bond is probably related to a competition between the rate of cyclization versus hydrogen abstraction from the tin hydride. Since the 5-exo-trig cyclization of the endo-2-(bicyclo[2.2.1]hept-2-en-5-yl)ethyl system is one of the fastest radical reactions 

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The two syntheses in Schemes 8.12 and 8.13 are essentially linear. They have rather different bond-sets, yet they have the same number of steps and the same number of bonds in the bond-sets (Scheme 13.33). Accordingly, the difference in the ratio between skeletal bond-forming steps and refunctionalization steps is minimal, arising solely from differences in the polycyclization cascades. Note that step (4) in the Danishefsky synthesis counts as a refunctionalization step, because the skeleton is only temporarily extended. 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

In the synthesis of the squalenoid glabrescol (72 originally attributed structure), containing five adjacent (all cis) THF rings, the necessary precursor of the polyepoxide cascade, the pentaepoxide 71, was achieved by epoxidation of each of the trisubstituted double bonds of the known (R)-2,3-dihydroxy-2,3-dihydrosqualene (70) by the Shi epoxidation approach (Scheme 8.18) [34]. Treatment of 71 with CSA at 0 °C and subsequent purification by column chromatography provided the pure polycyclic ether 72 by a cascade process reasonably initiated by the free secondary alcohol functionality [35a]. 

Closely related to the polyepoxide cascade procedure for the synthesis of polycyclic systems is Corey s biomimetic-type, nonenzymatic, oxirane-initiated (Lewis acid-promoted) cation-olefin polyannulation. By this strategy, compound 96, containing the tetracyclic core of scalarenedial, was constructed by exposure of the acyclic epoxy triene precursor 95 to MeAlCl2-promoted cyclization reaction conditions (Scheme 8.25) [45]. 

Epoxides are often encountered in nature, both as intermediates in key biosynthetic pathways and as secondary metabolites. The selective epoxidation of squa-lene, resulting in 2,3-squalene oxide, for example, is the prelude to the remarkable olefin oligomerization cascade that creates the steroid nucleus [7]. Tetrahydrodiols, the ultimate products of metabolism of polycyclic aromatic hydrocarbons, bind to the nucleic acids of mammalian cells and are implicated in carcinogenesis [8], In organic synthesis, epoxides are invaluable building blocks for introduction of diverse functionality into the hydrocarbon backbone in a 1,2-fashion. It is therefore not surprising that chemistry of epoxides has received much attention [9]. 

Malacria, M. (1996) Selective Preparation of Complex Polycyclic Molecules from Acyclic Precursors via Radical Mediated or Transition Metal-Catalyzed Cascade Reactions. Chemical Reviews, 96, 289-306. 

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

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

A new triethylamine-catalyzed cascade reaction of aromatic aldehydes and propiolates was developed to prepare various benzo[ >]furan-based polycyclic aromatics. Interestingly, the chemical outcome of this process depended on the reaction temperature and was selectively tailored by an appropriate choice of experimental conditions <06OL1241>. 

ArmentroutPB (1999) Gas-Phase Organometallic Chemistry. 4 1-45 Astruc D, Daniel M-C, Ruiz J (2006) Metallodendritic Exo-Receptors for the Redox Recognition of Oxo-Anions and Halides. 20 121-148 Aubert C, Fensterbank L, Gandon V, MalacriaM (2006) Complex Polycyclic Molecules from Acyclic Precursors via Transition Metal-Catalyzed Cascade Reactions. 19 259-294... 

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. 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

The various, complex, cascade reactions described above converted simple saturated and aromatic heterocycles into polycyclic pentathiepins and their chlorinated and rearranged derivatives this strikingly illustrates the extensive reactivity of S2CI2 and its complexes with bases, particularly DABCO. This reactivity encompassed dehydrogenation of tetrahydroaromatics, chlorination and sulfuration of aromatics and their conversion into SSCl derivatives. 

Opioid receptors. Direct binding of highly radioactive opiates has permitted localization of specific opiate receptors of several types.863-866 The three major types (p, 8, k) are all 7-helix receptors coupled to adenylate cyclase, K+ and Ca2+ channels, and the MAP kinase cascade.866 The p receptors bind morphine most tightly.867 8673 These receptors are found in various cortical and subcortical regions of the brain. Most narcotics are polycyclic in nature and share the grouping indicated in Fig. 30-30. However, the flexible molecule methadone binds to the same receptors.868 Among antagonists that block the euphoric effects of opiates the most effective is naloxone (Fig. 30-30). 

Figure 5.14. Synthesis of polycyclic structures using a ring-opening, ring-closing metathesis cascade [121].

Certain substituted, 1,6-enynes and related dienynes undergo palladium-catalyzed cycliza-tion to give polycyclic structures containing a three-membered ring via cascade carbopal-ladation (equation 156)343 34S. Transformation of 66 into 67 is representative346. 

There has been great interest in recent years in methods for the generation of azomethine ylides and in exploitation of these reactive species in tandem/cascade processes for the rapid assembly of polyaza, polycyclic, multifunctional systems. a-Diazo ketones have featured greatly in such studies, treatment with a catalytic amount of rhodium(II) acetate generating transient rhodium carbenoids. A very common feature of many investigations of this type is the occurrence of quite unexpected reactions. For example, treatment of the diazo ketone 1 with a catalytic amount of... 

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