Bicyclic enediynes

A similar procedure was used for the preparation of several bicyclic enediynes 78 from bis-iodonium salts 62 and alkynylstannanes (Scheme 36) [61]. This coupling reaction was recently utilized in the synthesis of novel dinu-clear complexes with a photochromic bridge [62]. 

The same group of workers has developed a method for the closure of the 3,4-bis(but-2-ynal)azetidinone 283 using Pedersen vanadium(n)-mediated pinacol coupling to give the vie-diol 284 from which it was possible to get the bicyclic enediyne in two steps and 63% overall yield from the diol <2000EJ0939> (see Section 2.04.7.2). 

Bicyclic enediynes were obtained from the Diels-Alder adducts of cyclopenta-diene or furan with bis phenyliodonium acetylene triflate and lithium alkynyl cuprates. In this case the reaction conditions were more demanding and yields less satisfactory. 

Great care should be exercised in these preparations, in order to exclude traces of moisture. To a stirred solution of the alkyne (6 mmol) in dichloromethane (50 ml) was added butyl lithium (2.4 ml of a 2.5 M solution in hexane) at - 70°C, under a positive pressure of nitrogen. After 10 min, cuprous cyanide (0.27 g, 3 mmol) was added and stirring continued for 2 h at — 40°C. The mixture was cooled to - 70°C and the iodonium salt (1 mmol) was added this mixture was allowed to warm to room temperature slowly and stirred for another 10 h. Then it was poured into a saturated aqueous solution of ammonium chloride (100 ml), extracted with dichloromethane and the organic layer was dried and concentrated. The residue was purified by filtration through a short silica column (hexane, then dichloromethane) solvent evaporation afforded pure bicyclic enediynes, in 36-69% yield. 

The synthetic potential of coupling reactions between vinyliodonium salts and organocuprates has not been exploited. However, some indication of their promise is provided by reported syntheses of bicyclic enediynes in the norbornadiene and 7-oxanor-bornadiene series from the appropriate bisiodonium triflates and lithium dialkynyl-cuprates (equation 221)148. 

Bicyclic enediynes,4 The key step in a synthesis of these encdiyncs is a TiCl4-catalyzcd Sakurai reaction of a conjugated allylsilanc (1) with the enonc 2 to provide 3 as a single product. This product, after conversion to the ketal, was cyclizcd to 4 by... 

An alternative approach to the bicyclic enediyne core of esperamicin utilizing an intramolecular Diels-Alder reaction was reported by Schreiber and co-workers (Scheme 7-45) [195-197]. This approach was initially hampered by an unfavorable regiochemical outcome in the Diels-Alder reaction (195 - 196), but was successfully corrected by a clever maneuver involving a Tsuchihashi pinacol rearrangement [198, 199] with concomitant diastereoselective acyloin shift to secure the desired bicyclic ring skeleton (197 - 198 - 199). 

Bicyclic enediynes. The ki catalyzed Sakurai reaction of a o 3 as a single product. This prodn... 

Bicyclic cis- and frans-isoxazolidinyldiynes have been prepared by intramolecular nitrone cycloaddition of the two side chains of an acyclic enediyne-nitrone precursor (Scheme 2.233) (731). 

The reaction of enediyne 74 in which the olefin moiety is located as a part of the cyclo-hexenyl ring proceeds through a cascade SiCaC bicyclization process, followed by /9-hydride elimination, to give tricyclic exo-silylmethylene-bis(cyclopentylidene) 75 in good yield (Eq. 21) [48]. 

An ideal artificial enediyne prodrug should be stable toward cycloaromatization. Therefore the ASE must be considerably higher than that calculated for 10-11. This can be realized by designing structural constraints that increase the steric strain of the product much more than that of the enediyne. Simple substituents are not, in general, able to diminish the reactivity adequately thus, stabilized enediyne analogs are typically ortho-fused or bridged bicyclic or polycyclic compounds. 

It is impossible to describe in detail in this chapter all the formidable synthetic efforts that have been dedicated to the total synthesis of natural and artificial enediynes. However, we will try to summarize here the main strategies that have been employed in the preparation of cyclic enediyne rings. In most cases complex bicyclic or polycyclic compounds have been prepared by one of these methodologies. 

Audrain, H. Skrydstrup, T. Ulibarri, G. Riche, C. Chiaroni, A. Grierson, D.S. Application and mechanistic studies of the [2,3]-Wittig rearrangement an approach to the bicyclic core structure of the enediyne antitumor antibiotics calicheamicin y/ and esperamicin-Ai. Tetrahedron 1994, 50, 1469-1502. 

Magnus and coworkers have concluded that the cyclization rate of enediynes depends on the strain energy of the transition state leading to the diyl (Scheme 16) [38]. They examined bicyclic systems 107 and 108, comparing their rates of cyclization and discovered that despite similar cd distances, substrate 107 cyclizes much faster. By performing calculations on a model system 111, they concluded that the greater strain energy of product 109 retards the rate of cyclization relative to 110. This work was carried out under the assumption that the transition state is product-like. 

This cycloallene was first prepared by Christl and co-workers from the bromofluoro-hydrocarbon 51 by treatment with methyl lithium. [58] The CeHe isomer does not survive the conditions of its generation but can be trapped with e. g. styrene to yield the bicyclic adduct 54. In the meantime a further route to 52 has been found, consisting in the thermal cyclization of l,3-hexdien-5-yne 53. [59] Hydrocarbon 53 is a close relative of 3-hexen-l,5-diyne 55, the parent enediyne system for which Bergman first described the cyclization 55->56 which later should carry his name. 

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