Cychzation, transannular

To study the effects of water and other solvents on titanocene(III)-mediated processes we used the transannular cychzation of epoxygerma-crolides as a model reaction [47]. Thus, we found that in anhydrous, non-halogenated solvents such as THF the reaction led selectively to decalins with an exocyclic double bond (Scheme 5). In an aqueous medium (THF/H2O), however, the characteristic lime green color of Cp2TiCl turned deep blue and the main product was a reduced decalin (Scheme 5). Under these conditions, water (either H2O or D2O) proved to be more effective than the toxic and expensive hydrogen-atom donor 1,4-cyclohexadiene for the reduction of tertiary radicals [47]. This is an unusual phenomenon in free-radical chemistry [48-50], subsequently exploited by us for the selective reduction of aromatic ketones as we shall see later [51,52]. 

Transannular cyclizations generally contribute to the enhancement of molecular rigidity and structural complexity, two properties often associated with biological activity of small molecules [114]. In this scenario, we found that the Cp2TiCl-mediated transannular cychzation of 1,10-epoxycostunolide, a homo chiral material accessible in (multi)gram quantities, provides a straightforward way for the enantiospecific synthesis of eudesmanolides such as (-i-)-reynosin (18) (Scheme 23) and (-i-)-3a-hydroxyreynosin [47]. 

The conventional acid-induced transannular cychzation of 1,10-epoxy-costunolide, via carbocationic chemistry, results in a eudesmanohde mix-... 

Dalgard JE, Rychnovsky SD. Memory of Chirality in the Transannular Cychzation of Cyclodecenyl Radicals. Org Lett. 2004 6(16) 2713—2716. 

One such example is the synthesis of ( )-jasmine ketolactone by Shimizu and Nakagawa. The transannular cychzation of macrocychc lactone 89 was initiated by treatment with NaH in toluene at 90°C to give ( )-jasmine ketolactone in 69% yield (Scheme 20.23). The reaction was highly diastereoselective as only the trans-isomtx was formed. 

SCHEME 20.38. The transannular cationic cychzation approach in the synthesis of capneUenes. 

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