Natural intramolecular couplings

Anodic C, C-coupling is a very powerful tool to synthesize cyclic compounds with high regio- and stereoselectivity. It involves inter- and intramolecular coupling of arylolefins, dienes, enolethers, phenol ethers, and aromatic amines and often opens a quick entry into complex natural products in a few steps. Although the mechanism is fully established in only a few cases, it does appear to involve the coupling of two radical cations at the site of their highest radical density and is further controlled by steric constraints. This important type of reaction is reviewed in Chap. 5 and in Refs. [89, 90]. 

One of the most synthetically useful anodic C-C bond forming reactions developed to date involves the intramolecular coupling of phenol derivatives with olefins. Yamamura has demonstrated that these reactions tend to lead to three classes of products (Scheme 22) [36]. The type of product generated depended strongly on both the nature and stereochemistry of the functional groups attached to the olefin moiety. For example, consider the two cyclization reactions illustrated in Scheme 23 [37]. In this experiment, the stereochemistry of the initial olefin substrate completely dictated the ring skeleton of the product. 

Intramolecular coupling reactions between nucleophilic olefins have also proven to hold potential as synthetically useful reactions. The first example of this type of reaction was reported by Shono and coworkers who examined the intramolecular coupling reaction of an enol acetate and a monosubstituted olefin (Scheme 41) [50]. This reaction was conducted in an effort to probe the nature of the radical cation intermediate generated from the anodic oxidation of... 

The nature of the intramolecular coupling terms arising from the breakdown of the BO approximation has been studied by Franck and Sponer,82 Kubo,83 Robinson and Frosch,87 McCoy, Hunt, and Ross,84-88 Lin and Bersohn,88,89 and Siebrand.90-93 What is the general form of these coupling terms, and what physical information do they contain ... 

With the optically active tetrahydroisoquinoline 79 in hand the total synthesis of (-)-ancistrocladine (1), and its naturally occurring atropisomer (-t-)-hamatine (92), was completed as shown in Scheme 11. Esterification of compound 79 with acid chloride 60 gave the ester 87 which smoothly underwent Pd(II) catalysed intramolecular coupling to yield the 5-1 coupled lactones 88 and 89 as a 3 1 mixture respectively. None of the possible 7-1 linked regioisomeric lactone was detected. These lactones are helicene-like atropisomers (not axially prostereogenic) but they... 

The intramolecular coupling of haloaryl- or halovinyl-linked ketones and aldehydes as well as other carbonyl species is a useful tool for the construction of cyclic compounds including natural products [38-41]. The synthesis of the precursor of a natural immunosuppressant, FR901483, is a recent example (Eq. 16)... 

Moeller synthesized tetrahydrofuran natural products (+)-linalool oxide <01OL2685> and (+)-nemorensic acid <01TL7163> by employing intramolecular coupling reactions of enol ether radical cations as well as ketene dithioacetal radical cations with oxygen nucleophiles. 

Intramolecular Coupling Reactions of Aldehydes and Ketones 6.2.2.1 Synthesis of Non-Natural Products... 

Doucet and coworkers reported the intramolecular coupling reaction of 2-bromobenzenesulfonic acid phenyl esters in the presence of a phosphine-free palladium catalyst (Scheme 4.16) [23]. One mole percentage of phosphine-free Pd (OAc)2 as the catalyst associated to KOAc promoted the intramolecular direct arylation via an sp C-H bond functionalization of several 2-bromobenzenesulfonic acid derivatives. The nature of the substituents on the phenol moiety was found to have a huge influence on the reaction. Electron-donating substituents favored the reaction, whereas electron-withdrawing substituents are unfavorable. As a very wide variety of phenols are commercially available, such a cyclization would provide a very simple access to functionalized sultones. 

Nitzan, A. and Jortner. J. (1971) What is the nature of intramolecular coupling responsible for internal conversion in large molecules Chem. Phys. Lett., 11, 458. 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

Our strategy is based on the premise that the 31-membered ring and the conjugated triene array of the natural product could be fashioned simultaneously by a tandem inter-/intramolecular Stille coupling. Moreover, the mild conditions under which Stille couplings can be performed fueled hopes that the crucial stitching cycliza-tion could be conducted on a fully deprotected seco bis(vinyl iodide) (see 145, Schemes 40 and 54) the stitching cyclization would thus be the final operation in the synthesis. 

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