Transannular activation

Chemistry and biological activity of artemisinin (sesquiterpene y-lactone with oxepane fragment and transannular peroxide bridge) and related antimalari-als 99H(51)1681. 

Catalyst 70 is very effective for the reaction of terminal alkenes, however 1,1-disubstituted olefins provide hydrosilylation products presumably, this is due to steric hindrance [45]. When a catalyst with an open geometry (78 or 79) is employed, 1,1-disubstituted alkenes are inserted into C-Y bonds to give quaternary carbon centers with high diastereoselectivities (Scheme 18). As before, initial insertion into the less hindered alkene is followed by cyclic insertion into the more hindered alkene (entry 1) [45]. Catalyst 79 is more active than is 78, operating with shorter reaction times (entries 2 and 3) and reduced temperatures. Transannular cyclization was possible in moderate yield (entry 4), as was formation of spirocyclic or propellane products... 

Raman spectroscopy is a useful probe for detecting transannular S - S interactions in bicyclic or cage S-N molecules or ions. The strongly Raman active vibrations occur at frequencies in the range 180-300 cm-1, and for S- -S distances in the range 2.4-2.7 A. On the basis of symmetry considerations, the Raman spectrum of the mixed sulfur-selenium nitride S2Se2N4 was assigned to the 1,5- rather than the 1,3- isomer.37... 

Similar low activities were found in the hydrogenation of 1-octene [47]. The use of [Ni(PPh3)2I2] in the hydrogenation of norbomadiene resulted in considerable amounts of nortricyclene, via transannular ring closure, whereas 1,5-cyclo-octadiene yielded bis-cyclo-[3.3.0]oct-2-ene. According to these authors, the re-... 

In a related experiment, a radical intermediate derived from the oxidation of an activated methylene group was used to trigger a transannular cyclization across an eight-membered ring (Scheme 14) [26], After cyclization, the reaction... 

The same models as for intermolccular processes are applied for intramolecular diastereoface differentiating double-bond additions. However, there are some advantages in the intramolecular version. Firstly, the entropy factor lowers the barrier of activation and allows reactions to proceed at lower temperatures, which increases the selectivity. Secondly, the cyclic transition states introduce the elements of ring strain and transannular interactions, which lead to enhanced differences between two diastereomorphous geometries. Both of these factors cooperate to increase the selectivity of the intramolecular reaction. For example, halolactonization, by definition, is an intramolecular process. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Levin and Hoffmann14 carried out their calculations on two trans-cyclooctene conformations, 1 and 2. To introduce the two conformations here and also on a number of simpler prototypes, one of them was twisted ethylene, using 29°, 20° and 10° torsion angles. They have suggested three possible sources for the optical activity of trans -cyclooctene the chirally disposed allylic substituents, the transannular portion of the methylene chain... 

The reaction of (25 R = Pr1) with HC1 has been found to give (26 X = C1) in quantitative yield as a result of transannular cyclization (Scheme 9) similar reactions occurred with H+-MeOH or H30+. Activation parameters, obtained by investigating the cyclization of (25) at different temperatures, are AH = 21 1 kcal mol-1 and AS = —9 2 cal mol-1 K 1. These results are compatible with an AdE2 mechanism.41... 

When subjected to the action of propanethiol under basic conditions (pH 9.2), jatrophone (2) undergoes a Michael reaction across its C8-C9 double bond, followed by facile transannular cyclization to give the tetracyclic diketone 3.2,9 The susceptibility of this enone part structure to conjugate addition has been proposed to constitute the event responsible for the pronounced biological activity of 2.9... 

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a,f)-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alkylation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a... 

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