Dienediyne

Enediynes with ethylene carbonate fragment in the synthesis of dienediyne models of the biradical-forming and DNA-cleaving natural neocarzinostatin chromophore 99SL657. 

The same authors also combined the [2+2+1] cycloaddihon with a Diels-Alder reaction [281]. For this multicyclization, the dienediyne 6/4-18 was treated with 5 mol% C02(C0)8 under 30 atm CO at 130 °C for 18 h to give the tetracyclic compound 6/4-19 (Scheme 6/4.6). 

Yields of the coupling products with alkynyl bromides are relatively low as compared with those obtained with allyl chloride or benzyl chloride. One reason for this is the instability of the product. The dienediynes 51 are slowly cyclized under the influence of light to give pentacyclic dimers 52 (Eq. 2.36), one of which has been characterized by X-ray analysis. 

The remaining alkenyl copper moiety in 50 can react intramolecularly with the carbon—carbon triple bond to give metallofulvene derivatives 53. However, the coupling of the intermediate with the second molecule of alkynyl halide would seem to be faster than the cyclization reaction. Therefore, the dienediyne is obtained as the major product. 

Reduction of enynes to (Z)-atkenes. Lindlar s catalyst is not useful as a hydrogenation catalyst for reduction of trienynes or of dienediynes. The best results can be obtained in CH3OH with zinc activated by successive treatment with Cu(OAc)2 (10%) and AgN03 (10%). This reduction results in conversion of the triple bond to a (Z)-double bond. The system does not reduce simple, nonactivated alkynes, and a-branched enynes are reduced slowly. The reduction is effected at 25° with (Z)-enynes, but temperatures of 45° are necessary for the (E)-isomers. Yields of pure tetraenes are 25-65%. 

Suffert J, Toussaint D (1997) Synthesis of a Cyclic Dienediyne Related to the Maduropeptin Chromophore. Tetrahedron Lett 38 5507... 

From a tactical perspective, early retrosynthetic removal of the epoxy dienediyne core must dominate all synthetic planning for (+ )-neocarzi-nostatin, since its presence in any intermediate will render that molecule highly susceptible to nucleophilic attack, and will jeopardise the success of all the remaining chemistry. In essence, it would be strategically advisable to install the epoxy dienediyne unit late in a forward total synthesis of ( + )-neocarzinostatin. 

However, in another contribution, Chung and coworkers realized the one-pot synthesis of [ S.5.5.6] fenestranes 42 via intramolecular cobalt-catalyzed tandem Pauson-Khand/Diels-Alder reactions of dienediynes 41 [44] (Scheme 21). 

Regioselective addition of 2-methoxyfuran and 2-trimethylsilyloxyfuran to chromium(O) alkynylcarbene complexes furnished interesting dienyne and dienediyne carboxylates <07AGE2610>. The reaction likely proceeded through a formal vinylogous Michael addition adduct, as illustrated in the following example. 

Four TES ethers were cleaved in the final step of an approach to N1999-A2, a member of the highly unstable enediynes.20 After low temperature dehydration of 17.1 via its triflate [Scheme 4.17], deprotection was implemented by treatment with trifluoroacetic acid in aqueous THE at 0 °C to give the target epoxy-dienediyne 17.2 in 45% yield for the two steps. rtrf-Butyldimethytsilyl ethers could not be removed without total destruction of the molecule. 

A particularly interesting application of this protocol, in conjunction with the direct cross-coupling with terminal acetylenes is shown in Scheme 5-2. Here, the first coupling occurs between the alkynyltin reagent 50 and the cyclized palladium intermediate 49 and is followed by the second direct coupling with the terminal acetylene 52 at the vinyl bromide moiety to yield unsymmetrical cyclic dienediyne 53 [32]. 

Scheme 5-2 Synthesis of unsymmetrical cyclic dienediyne 53 by stepwise cross-coupling reactions.

Nuss and co-workers have demonstrated that a tandem Heck cyclization-anion capture process can access substructures related to vitamin D [58] and the neocarzinostatin chromophore (162) (Scheme 6-28) [59]. In a one-pot procedure, diiodide 159 was converted into dienediyne 160 in low yield. In this reaction, the alkyne undergoes Heck... 

Workers from Hoffmann-La Roche have also devised a linear synthesis of racemic LTA4 methyl ester during the course of a synthesis of LTE4. They too employed a sulfonium salt (Scheme 3.22) in the epoxide-forming step to obtain a dienediyne epoxide. This step was made reasonably efficient by the use of a two-phase reaction system with a phase-transfer catalyst. Their sequence is also amenable to reasonable scale-up as they describe the preparation of 18 g of the epoxide mixture in a single reaction. A unique aspect of this synthesis is... 

Biosynthetic studies [70] with NCS chromophore showed that the C14 dienediyne ring skeleton incorporates six intact acetate units and two terminal acetate units which suffer C — C... 

Scheme 7-20 Synthesis of the epoxy dienediyne core of NCS chiomophore (Myers et al.).

Scheme 7-29 Falladiiun-mediated construction of a dienediyne related to NCS chromophore (Nuss et al.).

Although most work relating to the neocarzinostatin chromophore has concentrated upon the dienediyne core of the molecule, a number of studies concerning the naphthoate moiety have also appeared [175-179]. 

---