Ludger Ernst

In our effort to prepare [m.n]cyclophanes carrying functional groups in their molecular bridges, the thiacyclophanes 14, 19, 20, and 21 have been prepared by simple routes from the pseudo-gem dibromide 10a and the corresponding bis-thiol 10b. The triply-bridged bis-thia-cyclophanes 14, and 19-21 were characterized by their spectroscopic data as well as by X-ray structural analyses. The meta-isomer 20 was oxidized to the bis-sulfone 23, which on flash vacuum pyrolysis (FVP) yielded a product mixture presumably containing the hydrocarbon 26 with a cleaved molecular bridge. Subjecting 23 to Ramberg-Bäcklund conditions (CCl₄, NaOH, phase transfer catalysis) provided the chloride 24 in poor yield (9%), a [2.2]paracyclophane in which the new molecular bridge is fully conjugated.

Starting with the parent compound [2.2.2]paracyclophane several routes were developed to synthesize its 4-vinyl derivative. From the 4-aldehyde and the bromomethyl derivative the stilbenophanes were prepared which photocyclize to the phenanthrenophanes. A new route to a bridged ketone was developed which was subjected to the addition of phenyllithium and to typical aromatic substitution reactions (inter alia Rieche formylation, Friedel–Crafts acylation). Bromination of the bridged ketone yielded an unusual tropone derivative. Electrophilic substitution reactions were also carried out for the bridged hydrocarbon, the reduction product of the bridged ketone. For both the bridged ketone and the bridged hydrocarbon the electrophilic substitutions occur regioselectively, favoring the introduction of the new substituent in a syn orientation to the bridging keto and methylene group, respectively. 1 Introduction 2 Results and Discussion 2.1 4-Vinyl[2.2.2]paracyclophane (5) 2.2 [2.2.2]Paracyclophane (2a) as Part of Extended Aromatic Systems 2.3 The Preparation of 5,12-Methano[2.2.2]paracyclophan-25-one (3) 2.4 Selected Reactions with 5,12-Methano[2.2.2]paracyclophan-25-one (3) 2.4.1 Reactions of 3 with Metalorganic Reagents 2.4.2 Friedel–Crafts Reactions with 3 2.4.3 Bromination of 3 2.5 Selected Reactions with 5,12-Methano[2.2.2]paracyclophane (31) 2.5.1 Friedel–Crafts Reactions 2.5.2 Bromination of 31 3 Conclusion

In plants, prenylation of metabolites is widely distributed to generate compounds with efficient defense potential and distinct pharmacological activities profitable to human health. Prenylated compounds are formed by members of the prenyltransferase (PT) superfamily, which catalyze the addition of prenyl moieties to a variety of acceptor molecules. Cell cultures of Hypericum calycinum respond to elicitor treatment with the accumulation of the prenylated xanthone hyperxanthone E. A cDNA encoding a membrane-bound PT (HcPT) was isolated from a subtracted cDNA library and transcript preparations of H. calycinum. An increase in the HcPT transcript level preceded hyperxanthone E accumulation in cell cultures of H. calycinum treated with elicitor. The HcPT cDNA was functionally characterized by expression in baculovirus-infected insect cells. The recombinant enzyme catalyzed biosynthesis of 1,3,6,7-tetrahydroxy-8-prenylxanthone through regiospecific C–8 prenylation of 1,3,6,7-tetrahydroxyxanthone, indicating its involvement in hyperxanthone E formation. The enzymatic product shared significant structural features with the previously reported cholinesterase inhibitor γ-mangostin. Thus, our findings may offer a chance for semisynthesis of new active agents to be involved in the treatment of Alzheimer’s disease.

The [2.2]paracyclophane moiety is used as a spacer to connect the ends of a hex‐3‐ene‐1,5‐diyne unit, a π‐system that on thermolysis usually cycloaromatizes to a benzene ring (Bergman cyclization). For the preparation of the pseudo‐geminally‐bridged system 9, the diacetylene 3 was chain‐extended to the diol 16, which after conversion to the pseudo‐geminal dibromide 17 was ring‐closed by treatment with LiHMDS/HMPA to the [2.2]paracyclophane enediyne 9. Whereas the McMurry coupling of the pseudo‐ortho bisaldehyde 24 resulted in the formation of the hexadienyne‐bridged cyclophane 27, the pseudo‐ortho‐bridged hydrocarbon 11 was obtained by preparing first the diol 28 from 24, converting the latter into the dioxolane 29, which in the last step furnished the olefin 11 by treatment with Tf₂O/EtN(iPr)₂. The authentic Bergman product 10 of the pseudo‐gem‐bridged hexenediyne 9 was synthesized by a conventional sequence starting from the ethynyl formyl substrate 18. Since the pseudo‐ortho‐enediyne‐bridged hydrocarbon 11 is thermally labile, its benzannelated derivate 34 was prepared. No classical Bergman cyclization reactions could be observed for any of the [2.2]paracyclophane‐bridged hexenediynes prepared here. In the pseudo‐gem‐series the fulvenes 14 and 15 were the only products that could be identified under thermal conditions (McMurry coupling); the benzannelated substrate 34 gave the benzofulvene‐bridged cyclophane 36 on photolysis. Bergman cyclizations yielding fulvene derivatives are extremely rare. The mechanism of the cyclization of 9 and 34 is discussed, using compliance constants. The structure assignments of the hydrocarbons synthesized in this study are based on spectroscopic studies as well as X‐ray structural analyses for 9, 10, 11, 27, and 34.